Substituted pyrimidinyl oxime kinase inhibitors

ABSTRACT

The present invention is directed to substituted pyrimidine compounds of formula (I): 
                         
and forms thereof, their synthesis and use for treating, preventing or ameliorating a chronic or acute protein kinase mediated disease, disorder or condition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/609,450, filed Dec. 12, 2006, which claims the benefit of U.S.Provisional Patent Application Ser. No. 60/752,633, filed Dec. 21, 2005,the entireties of which are incorporated herein by reference for allpurposes.

FIELD OF THE INVENTION

The present invention is in the area of substituted pyrimidine compoundsand forms thereof and methods of preparation and use thereof as kinaseinhibitors.

BACKGROUND OF THE INVENTION

In general, protein kinases are the largest set of structurally relatedphosphoryl transferases, have highly conserved structures and catalyticfunctions and may be categorized into families by the substrates theyphosphorylate (e.g., protein-tyrosine, protein-serine/threonine,histidine and the like) and are responsible for the control of a widevariety of cellular signal transduction processes.

Examples of protein-tyrosine kinases include, but are not limited to,Irk, IGFR-1, Zap-70, Bmx, Btk, CHK (Csk homologous kinase), CSK(C-terminal Src Kinase), Itk-1, Src (c-Src, Lyn, Fyn, Lck, Syk, Hck,Yes, Blk, Fgr and Frk), Tec, Txk/Rlk, Abl, EGFR (EGFR-1/ErbB-1,ErbB-2/NEU/HER-2, ErbB-3 and ErbB-4), FAK, FGF1R (also FGFR1 or FGR-1),FGF2R (also FGR-2), MET (also Met-1 or c-MET), PDGFR (α and β), Tie-1,Tie-2 (also Tek-1 or Tek), VEGFR1 (also FLT-1), VEGFR2 (also KDR),FLT-3, FLT-4, c-KIT, JAK1, JAK2, JAK3, TYK2, LOK, RET, TRKA, PYK2, ALK(Anaplastic Lymphoma Kinase), EPHA (1-8), EPHB (1-6), RON, Fes, Fer orEPHB4 (also EPHB4-1).

Examples of protein-serine/threonine kinases include, but are notlimited to, Ark, ATM (1-3), CamK (1-IV), CamKK, Chk1 and 2 (Checkpointkinases), CK1, CK2, Erk, IKK-I (also IKK-ALPHA or CHUK), IKK-2 (alsoIKK-BETA), Ilk, Jnk (1-3), LimK (1 and 2), MLK3Raf (A, B, and C), CDK(1-10), PKC (including all PKC subtypes), Plk (1-3), NIK, Pak (1-3),PDK1, PKR, RhoK, RIP, RIP-2, GSK3 (α and β), PKA, P38, Erk (1-3), PKB(including all PKB subtypes) (also AKT-1, AKT-2, AKT-3 or AKT3-1),IRAK1, FRK, SGK, TAK1 or Tp1-2 (also COT).

Protein kinases play very important roles in the normal regulation ofcell growth. However, as a result of dysregulation of the tyrosinekinases (receptor or non-receptor) or the ligands of the receptortyrosine kinases, signaling can become deregulated, resulting inuncontrolled cell proliferation leading to cancer or a related disease,disorder or syndrome.

Protein kinases catalyze and regulate the process of phosphorylation,whereby the kinases covalently attach phosphate groups to proteins orlipid targets in response to a variety of extracellular signals:hormones, neurotransmitters, growth and differentiation factors, cellcycle events, environmental stresses, nutritional stresses and the like.

Phosphorylation modulates or regulates a variety of cellular processessuch as proliferation, growth, differentiation, metabolism, apoptosis,motility, transcription, translation and other signaling processes.Defective control of protein phosphorylation due to unregulated cellularmitosis, unregulated cell proliferation and upregulated kinase activityhas been implicated in a number of diseases and disease conditions, suchas osteoarthritis, rheumatoid arthritis, synovial pannus invasion inarthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus,diabetic angiopathy, diabetic retinopathy, retinal vessel proliferation,inflammatory bowel disease, Crohn's disease, ulcerative colitis, bonediseases, transplant or bone marrow transplant rejection, lupus, chronicpancreatitis, cachexia, septic shock, fibroproliferative anddifferentiative skin diseases or disorders, central nervous systemdiseases, neurodegenerative diseases, disorders or conditions related tonerve damage and axon degeneration subsequent to a brain or spinal cordinjury, acute or chronic cancer, ocular diseases, viral infections,heart disease, lung or pulmonary diseases or kidney or renal diseases.Therefore, kinase inhibitors have potential use as therapeutic agents.

The term “myasthenia gravis” means a disease having the characteristicfeature of easy fatigue of certain voluntary muscle groups on repeateduse. Muscles of the face or upper trunk are especially likely to beaffected. In most and perhaps all cases, the disease is due to thedevelopment of autoantibodies against the acetylcholine receptor inneuromuscular junctions. Immunization of animals with this receptorprotein leads to a disease with the features of myasthenia gravis.

In reference to “synovial pannus invasion in arthritis”, the term“pannus” means a disease whereby vascularised granulation tissue rich infibroblasts, lymphocytes and macrophages, derived from synovial tissue,overgrows the bearing surface of the joint in rheumatoid arthritis andis associated with the breakdown of the articular surface.

The tyrosine kinases can further be categorized by whether they arereceptor tyrosine kinases or non-receptor tyrosine kinases. The receptortyrosine kinases span the cell membrane with a ligand interacting domainprotruding from the cell, with a hydrophobic trans-membrane domain, anda cytoplasmic domain that contains the catalytic kinase domain and otherregulatory sequences. Non-receptor tyrosine kinases are oftenmyristylated or modified by the addition of other hydrophobic moietiesthat allow them to be anchored to the cell membrane.

The epidermal growth factor receptor (EGFR) tyrosine-kinase familyincludes the receptors EGFR (also referred to as EGFR-1 or Erb-B1),HER-2 (or neu), EGFR3 and EGFR4. Epidermal Growth Factor (EGF),Transforming Growth Factor-α (TGF-α) and the HER-2 ligand heregulin arethree of the ligands that bind to the EGFR receptors.

For example, EGFR overexpression or mutation of one or more EGFR kinasefamily members has been commonly involved in cancer and other diseasescharacterized by uncontrolled or abnormal cell growth. Deregulation ofEGFR has also been associated with epidermoid tumors, head and necktumors, breast tumors and tumors involving other major organs, such asthe lungs and gastrointestinal tract. The clinically prevalent cancersrelated to EGFR include lung, gastric and head and neck cancer (Klijn JG, Berns P M, Schmitz P I and Foekens J A; The clinical significance ofepidermal growth factor receptor (EGF-R) in human breast cancer: areview on 5232 patients, Endocr. Rev., 1992, 13, 3-17; Salomon D andGullick W; The erbB family of receptors and their ligands: Multipletargets for therapy, Signal, 2001, 2, 4-11).

In treating cancers of the head such as brain cancers and the like, theability of small molecule EGFR inhibitors to penetrate the blood brainbarrier could have therapeutic advantages since EGFR is oftenoverexpressed in primary brain tumors and also in breast and non-smallcell lung carcinomas that frequently metastasize to the brain (EckstrandA J, Sugawa N, James C D and Collins V P; Amplified and rearrangedepidermal growth factor receptor genes in human glioblastomas revealdeletions of sequences encoding portions of the N- and/or C-terminaltails, Proc. Acad. Natl. Sci. USA, 1992, 89, 4309-4313; and, WickstrandC J, Hale L P, Batra S K, Hill M L, Humphrey P A, Kurpad S N, McLendon RE, Moscatello D, Pegram C N, Reist C J, Traweek S T, Wong A J, ZalutskyM R and Bigner, D D; Monoclonal antibodies against EGFRvIII are tumorspecific and react with breast and lung carcinomas and malignantgliomas, Cancer Res., 1995, 55, 3140-3148).

Diseases associated with increased EGFR expression include proliferativeglomerulonephritis, diabetes-induced renal disease and chronicpancreatitis.

EGFR inhibitors tested in neurite outgrowth assays have activity inpromoting neurite outgrowth in both cerebellar granule cells and dorsalroot ganglion neurons, likely by acting directly on neurons to blockneuronal inhibitory responses to myelin inhibitors, and thus an EGFRinhibitor may have potential use for promoting axon regeneration afterbrain and spinal cord injury (V. Koprivica, et al, EGFR activationmediates inhibition of axon regeneration by myelin and chondroitinsulfate proteoglycans, Science, 2005, 310, 106).

HER1 and HER2 overexpression has been implicated in a variety ofcancers, such as bladder, breast, colorectal, endometrial, esophageal,gastric (stomach), glioma head and neck, lung (non-small cell lungcancer), ovarian, pancreatic, renal and prostate cancer.

Comparing the overexpression of HER1 and HER2 in tumors, according toorder of prevalence, HER1 overexpression is found in breast, renal cell,lung, colorectal, head and neck, ovarian, pancreatic, glioma, bladder,esophageal, gastric, endometrial and cervical cancer tumors; incontrast, HER2 overexpression is found in esophageal, head and neck,lung, gastric, renal cell, breast, bladder, ovarian and colorectal,prostate and endometrial cancer tumors (Horizons in Cancer Therapeutics:From Bench to Bedside, Signal Transduction Inhibitors, 2001, 2(2), ISSN1532-3048).

While the degree of HER2 overexpression in breast and ovarian cancer isnot as great as in some other cancers, HER2 has been found to beresponsible for these clinically prevalent cancers (Slamon D J, Clark GM, Wong S G, Levin W J, Ullrich A and McGuire W L; Human breast cancer:Correlation of relapse and survival with amplification of HER-2/neuoncogene, Science, 1987, 235, 177-82; Slamon D J, Godolphin W, Jones LA, Holt J A, Wong S G, Keith D E, et al; Studies of the HER-2/neuproto-oncogene in human breast and ovarian cancer, Science, 1989, 244,707-712; Hetzel D J, Wilson T O, Keeney G L, Roche P C, Cha S S andPodrantz K C; HER-2/neu expression: A major prognostic factor inendometrial cancer, Gynecol. Oncol., 1992, 47, 179-85).

Furthermore, patients with HER-2 overexpressing breast cancer frequentlyexperience metastases to the brain (Kirsch D G and Hochberg F H;Targeting HER-2 in brain metastases from breast cancer, Clin. Can. Res.,2003, 9, 5435-5436). These patients have an extremely poor prognosis andintracerebral tumors are often the cause of death. Autopsy revealed that20-30% of patients who die of breast cancer have brain metastases(Grossi P M, Ochiai H, Archer G E, McLendon R E, Zalutsky M R, FriedmanA H, Friedman H S, Bigner D D and Sampson J H; Efficacy of intracerebralmicroinfusion of trastuzumab in an athymic rat model of intracerebralmetastatic breast cancer, Clin. Can. Res., 2003, 9, 5514-5520).

Human cytomegalovirus (CMV) is a widespread opportunistic human herpesvirus that causes severe and fatal diseases in those who are immunecompromised and in transplant recipients. CMV is also a leading cause ofatherosclerosis and virally mediated birth defects. The human CMV usesthe EGFR receptor to enter cells during infection, EGFR isautophosphorylated and the downstream signal transduction pathwaycomponents are activated; however, the EGFR specific inhibitortyrphostin AG1478 has been shown to reduce the viral load in cells thatwere infected in the presence of the tyrphostin (Wang X, et al., Nature,24 Jul. 2003, Vol. 424, 456-461). Accordingly, potent EGFR selectiveinhibitors may be useful in anti-CMV therapy.

Certain oxime substituted pyrimidines are registered by the ChemicalAbstracts Society (CAS) such as 4,6-diamino-5-pyrimidinecarboxaldehydeoxime (CAS Registry No.: 109831-69-8) andN,N-dimethyl-5-[(methylimino)methyl]-4,6-pyrimidinediamine (CAS RegistryNo.: 14160-97-5) and described in Heterocycles, 1987, 25(1), 343-5.Certain references describe substituted pyrimidine compounds such asUnited States patents: U.S. Pat. No. 6,080,750, U.S. Pat. No. 6,107,301and U.S. Pat. No. 6,833,378.

There is a need for potent small-molecule kinase inhibitors of one ormore of the EGFR, HER-1, HER-2 kinase proteins and the like possessinganti-tumor cell proliferation activity, and as such are useful fortreating or ameliorating a EGFR, HER-1 or HER-2 kinase receptormediated, angiogenesis-mediated or hyperproliferative disorder.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of formula (I):

and forms thereof, wherein R_(A), R₂, R₃, R₄, R₅, R₆, R₇, L and Ar areas defined herein.

An example of the present invention includes a compound of formula (I)and forms thereof as a protein kinase inhibitor.

An example of the present invention includes a prodrug form of acompound of formula (I) and forms thereof as a protein kinase inhibitor.

An example of the present invention includes a metabolite form of acompound of formula (I) and forms thereof as a protein kinase inhibitor.

An example of the present invention includes use of a compound offormula (I) and forms thereof as an inhibitor of a protein kinase suchas EGFR, HER-1, HER-2 and the like comprising contacting the proteinkinase domain or receptor with the compound.

An example of the present invention includes the use of a compound offormula (I) and forms thereof as a pharmaceutical composition, medicineor medicament for treating, preventing or ameliorating a kinase mediateddisease, disorder or condition.

An example of the present invention includes the use of a compound offormula (I) and forms thereof as a medicament.

An example of the present invention includes the use of a prodrug of acompound of formula (I) and forms thereof as a pharmaceuticalcomposition, medicine or medicament for treating, preventing orameliorating a kinase mediated disease, disorder or condition.

An example of the present invention includes the use of a prodrug of acompound of formula (I) and forms thereof as a medicament.

The present invention is further directed to a method for treating,preventing or ameliorating a chronic or acute protein kinase mediateddisease, disorder or condition in a subject in need thereof comprisingadministering to the subject an effective amount of a compound offormula (I) and forms thereof.

An example of the present invention includes a method for treating,preventing or ameliorating a chronic or acute protein kinase mediateddisease, disorder or condition in a subject in need thereof comprisingadministering to the subject an effective amount of a prodrug of acompound of formula (I) and forms thereof.

These and other aspects and advantages of the invention, which willbecome apparent in light of the detailed description below, are achievedthrough use of the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound of formula (I):

and forms thereof, wherein

-   L is selected from a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl;-   Ar is selected from aryl, heteroaryl, benzofused-heterocyclyl or    benzofused-C₃₋₁₂cycloalkyl;-   R_(A) is selected from C═N—O—R₁, cyano or an R₁ substituted    oxadiazole;-   R₁ is selected from hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl, C₁₋₈alkoxy,    C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl,    C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,    aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,    heterocyclyl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl    or heteroaryl-C₁₋₈alkyl,-   wherein aryl-C₁₋₈alkyl is optionally substituted on aryl with one,    two, three, four or five substituents each selected from hydroxy,    C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino or C₁₋₈alkoxycarbonyl,    and-   wherein heterocyclyl-C₁₋₈alkyl is optionally substituted on    heterocyclyl with one, two, three or four substituents each selected    from hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino or    C₁₋₈alkoxycarbonyl;-   R₂ is selected from hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and-   R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen, halogen,    hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,    hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,    C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,    carboxy, C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl,    thio-C₁₋₈alkyl, substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl,    aryloxy, aryl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy,    aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryl, heteroaryloxy,    heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,    benzofused-heterocyclyl or heterocyclyl,-   wherein phosphonic acid is substituted on the phosphorous atom with    two substituents selected from hydroxy or C₁₋₈alkoxy,-   wherein aryl, aryloxy, aryl-amino, aryl-C₁₋₈alkyl and    aryl-C₁₋₈alkoxy is each optionally substituted on aryl with one,    two, three, four or five substituents each selected from cyano,    halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with one or two oxo substituents, and-   wherein heteroaryl, heteroaryl-amino-sulfonyl and heteroaryloxy is    each optionally substituted on heteroaryl with one, two, three, four    or five substituents each selected from C₁₋₈alkyl, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl or C₁₋₈alkoxycarbonyl.

The present invention is directed to a compound of formula (II):

and forms thereof, wherein

-   L is selected from a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl;-   Ar is selected from aryl, heteroaryl, benzofused-heterocyclyl or    benzofused-C₃₋₁₂cycloalkyl, wherein the benzene ring portion of the    benzofused ring system is attached to the L variable;-   R_(A) is selected from C═N—O—R₁ or cyano;-   R₁ is selected from hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl, C₁₋₈alkoxy,    C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl,    C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,    aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,    heterocyclyl-carbonyl-C₁₋₈alkyl or heteroaryl-C₁₋₈alkyl,-   wherein aryl-C₁₋₈alkyl is optionally substituted on aryl with one,    two, three, four or five substituents each selected from hydroxy,    C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino or C₁₋₈alkoxycarbonyl,    and-   wherein heterocyclyl-C₁₋₈alkyl is optionally substituted on    heterocyclyl with one, two, three or four substituents each selected    from hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino or    C₁₋₈alkoxycarbonyl;-   R₂ is selected from hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and-   R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen, halogen,    hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,    hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl, C₁₋₈alkoxycarbonyl,    C₃₋₁₂cycloalkyl, aryl, aryloxy, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy,    aryl-amido, heteroaryl, heteroaryloxy, heteroaryl-C₁₋₈alkoxy or    heterocyclyl,-   wherein aryl, aryloxy, aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy is each    optionally substituted on aryl with one, two, three, four or five    substituents each selected from cyano, halogen, hydroxy, C₁₋₈alkyl,    C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl or C₁₋₈alkoxycarbonyl, and-   wherein heteroaryl and heteroaryloxy is each optionally substituted    on heteroaryl with one, two, three, four or five substituents each    selected from C₁₋₈alkyl, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    carboxy, C₁₋₈acyl or C₁₋₈alkoxycarbonyl.

An example of a compound of formula (I) and forms thereof includes acompound wherein R_(A) is C═N—O—R₁.

An example of a compound of formula (I) and forms thereof includes acompound wherein R_(A) is cyano.

An example of a compound of formula (I) and forms thereof includes acompound wherein R_(A) is an R₁ substituted oxadiazole.

An example of a compound of formula (I) and forms thereof includes acompound wherein R₁ is selected from hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl,C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl,C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,heterocyclyl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl orheteroaryl-C₁₋₈alkyl,

-   wherein aryl-C₁₋₈alkyl is optionally substituted on aryl with a    substituent selected from hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino,    C₁₋₈alkyl-amino or C₁₋₈alkoxycarbonyl, and-   wherein heterocyclyl-C₁₋₈alkyl is optionally substituted on    heterocyclyl with a substituent selected from hydroxy, C₁₋₈alkyl,    C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino or C₁₋₈alkoxycarbonyl.

An example of a compound of formula (I) and forms thereof includes acompound wherein R₁ is selected from hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl,C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl,C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,heterocyclyl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl orheteroaryl-C₁₋₈alkyl,

-   wherein aryl-C₁₋₈alkyl is optionally substituted on aryl with    C₁₋₈alkoxy, and-   wherein heterocyclyl-C₁₋₈alkyl is optionally substituted on    heterocyclyl with hydroxy or C₁₋₈alkoxycarbonyl.

An example of a compound of formula (I) and forms thereof includes acompound wherein R₁ is selected from hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl,C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,heterocyclyl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl orheteroaryl-C₁₋₈alkyl,

-   wherein aryl-C₁₋₈alkyl is optionally substituted on aryl with    C₁₋₈alkoxy, and-   wherein heterocyclyl-C₁₋₈alkyl is optionally substituted on    heterocyclyl with hydroxy or C₁₋₈alkoxycarbonyl.

An example of a compound of formula (I) and forms thereof includes acompound wherein R₂ is selected from hydrogen.

An example of a compound of formula (I) and forms thereof includes acompound wherein R₂ is selected from C₁₋₈alkyl.

An example of a compound of formula (I) and forms thereof includes acompound wherein R₂ is selected from C₁₋₈alkoxy.

An example of a compound of formula (I) and forms thereof includes acompound wherein R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen,halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy,cyano-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl, carboxy,C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl,substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl, aryloxy, aryl-amino,aryl-C₁₋₈ alkyl, aryl-C₁₋₈alkoxy, aryl-carbonyl-C₁₋₈alkyl, aryl-amido,heteroaryl, heteroaryloxy, heteroaryl-C₁₋₈alkoxy,heteroaryl-amino-sulfonyl, benzofused-heterocyclyl or heterocyclyl,

-   wherein phosphonic acid is substituted on the phosphorous atom with    two C₁₋₈alkoxy substituents,-   wherein aryl, aryl-amino, aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy is each    optionally substituted on aryl with one or two substituents each    selected from cyano, halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino,    C₁₋₈alkyl-amino, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl or    C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with two oxo substituents, and-   wherein heteroaryl-amino-sulfonyl and heteroaryloxy is each    optionally substituted on heteroaryl with one or two substituents    each selected from C₁₋₈alkyl, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl or C₁₋₈alkoxycarbonyl.

An example of a compound of formula (I) and forms thereof includes acompound wherein R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen,halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy,cyano-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl, carboxy,C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl,substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl, aryloxy, aryl-amino,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy, aryl-carbonyl-C₁₋₈alkyl, aryl-amido,heteroaryl, heteroaryloxy, heteroaryl-C₁₋₈alkoxy,heteroaryl-amino-sulfonyl, benzofused-heterocyclyl or heterocyclyl,

-   wherein phosphonic acid is substituted on the phosphorous atom with    two C₁₋₈alkoxy substituents,-   wherein aryl, aryl-amino, aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy is each    optionally substituted on aryl with one or two substituents each    selected from cyano, halogen, C₁₋₈alkoxy or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with two oxo substituents, and-   wherein heteroaryl-amino-sulfonyl and heteroaryloxy is each    optionally substituted on heteroaryl with one or two C₁₋₈alkyl    substituents.

An example of a compound of formula (I) and forms thereof includes acompound wherein R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen,halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkyl,halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl, C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl, C₁₋₈alkoxy-imino-C₁₋₈alkyl,C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl, C₁₋₈acyl, C₁₋₈acyl-amino,C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl, substituted phosphonic acid,C₃₋₁₂cycloalkyl, aryl, aryloxy, aryl-amino, aryl-C₁₋₈alkyl,aryl-C₁₋₈alkoxy, aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryloxy,heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,benzofused-heterocyclyl or heterocyclyl,

-   wherein phosphonic acid is substituted on the phosphorous atom with    two C₁₋₈alkoxy substituents,-   wherein aryl, aryl-amino, aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy is each    optionally substituted on aryl with one or two substituents each    selected from cyano, halogen, C₁₋₈alkoxy or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with two oxo substituents, and-   wherein heteroaryl-amino-sulfonyl and heteroaryloxy is each    optionally substituted on heteroaryl with one or two C₁₋₈alkyl    substituents.

An example of a compound of formula (I) and forms thereof includes acompound wherein

-   L is selected from a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl;-   Ar is selected from aryl, heteroaryl, benzofused-heterocyclyl or    benzofused-C₃₋₁₂cycloalkyl;-   R_(A) is selected from C═N—O—R₁, cyano or an R₁ substituted    oxadiazole;-   R₁ is selected from hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl,    C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,    aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,    heterocyclyl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl    or heteroaryl-C₁₋₈alkyl,-   wherein aryl-C₁₋₈alkyl is optionally substituted on aryl with    C₁₋₈alkoxy, and-   wherein heterocyclyl-C₁₋₈alkyl is optionally substituted on    heterocyclyl with hydroxy or C₁₋₈alkoxycarbonyl;-   R₂ is selected from hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and-   R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen, halogen,    hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkyl, halo-C₁₋₈alkoxy,    cyano-C₁₋₈alkyl, C₁₋₈alkyl-amino,    C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,    C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,    C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl,    substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl, aryloxy,    aryl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy,    aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryloxy,    heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,    benzofused-heterocyclyl or heterocyclyl,-   wherein phosphonic acid is substituted on the phosphorous atom with    two C₁₋₈alkoxy substituents,-   wherein aryl, aryl-amino, aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy is each    optionally substituted on aryl with one or two substituents each    selected from cyano, halogen, C₁₋₈alkoxy or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with two oxo substituents, and-   wherein heteroaryl-amino-sulfonyl and heteroaryloxy is each    optionally substituted on heteroaryl with one or two C₁₋₈alkyl    substituents.

An example of a compound of formula (I) and forms thereof includes acompound wherein

-   L is selected from a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl;-   Ar is selected from phenyl, naphthalenyl,    1,2,3,4-tetrahydro-naphthalenyl, 5,6,7,8-tetrahydro-naphthalenyl,    pyridinyl, pyridiminyl, indazolyl, indolyl, benzofuranyl,    benzoimidazolyl, benzothiazolyl, benzo[1,3]dioxolyl,    2,3-dihydro-indolyl, 1,2,3,4-tetrahydro-phthalazinyl or indanyl;-   R_(A) is selected from C═N—O—R₁, cyano or an R₁ substituted    oxadiazole;-   R₁ is selected from hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl,    C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl, phenyl-C₁₋₈alkyl,    phenoxy-C₁₋₈alkyl, morpholin-4-yl-C₁₋₈alkyl, piperidinyl-C₁₋₈alkyl,    morpholin-4-yl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl    or pyridinyl-C₁₋₈alkyl,-   wherein phenyl-C₁₋₈alkyl is optionally substituted on phenyl with    C₁₋₈alkoxy, and-   wherein piperidinyl-C₁₋₈alkyl is optionally substituted on    piperidinyl with hydroxy or C₁₋₈alkoxycarbonyl;-   R₂ is selected from hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and-   R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen, halogen,    hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkyl, halo-C₁₋₈alkoxy,    cyano-C₁₋₈alkyl, C₁₋₈alkyl-amino,    C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,    C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,    C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl,    substituted phosphonic acid, cyclohexyl, phenyl, phenoxy,    phenyl-amino, phenyl-C₁₋₈alkyl, phenyl-C₁₋₈alkoxy,    aryl-carbonyl-C₁₋₈alkyl, phenyl-amido, pyridinyloxy,    heteroaryl-C₁₋₈alkoxy, pyridimin-2-yl-amino-sulfonyl,    pyrazin-2-yl-amino-sulfonyl, benzofused-heterocyclyl or    morpholin-4-yl, wherein phosphonic acid is substituted on the    phosphorous atom with two C₁₋₈alkoxy substituents,-   wherein phenyl, phenyl-amino, phenyl-C₁₋₈alkyl and phenyl-C₁₋₈alkoxy    is each optionally substituted on aryl with one or two substituents    each selected from cyano, halogen, C₁₋₈alkoxy or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with two oxo substituents, and-   wherein pyridimin-2-yl-amino-sulfonyl, pyrazin-2-yl-amino-sulfonyl    and pyridinyloxy is each optionally substituted with one or two    C₁₋₈alkyl substituents.

An example of a compound of formula (I) and forms thereof includes acompound wherein

-   L is a bond;-   Ar is selected from phenyl, 1,2,3,4-tetrahydro-naphthalenyl,    pyridinyl, indazolyl or indolyl;-   R_(A) is selected from C═N—O—R₁ or cyano;-   R₁ is selected from hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl,    hydroxy-C₁₋₈alkyl, morpholin-4-yl-C₁₋₈alkyl or    piperidinyl-C₁₋₈alkyl;-   R₂ is hydrogen; and-   R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen, halogen,    phenoxy, phenyl-C₁₋₈alkyl or phenyl-C₁₋₈alkoxy,-   wherein phenyl-C₁₋₈alkyl is optionally substituted on phenyl with    halogen.

The present invention is further directed to a compound of formula (Ia):

and forms thereof, wherein

-   L is selected from a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl;-   R₁ is selected from hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl, C₁₋₈alkoxy,    C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl,    C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,    aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,    heterocyclyl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl    or heteroaryl-C₁₋₈alkyl,-   wherein aryl-C₁₋₈alkyl is optionally substituted on aryl with one,    two, three, four or five substituents each selected from hydroxy,    C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino or C₁₋₈alkoxycarbonyl,    and-   wherein heterocyclyl-C₁₋₈alkyl is optionally substituted on    heterocyclyl with one, two, three or four substituents each selected    from hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino or    C₁₋₈alkoxycarbonyl;-   R₂ is selected from hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and-   R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen, halogen,    hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,    hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,    C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,    carboxy, C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl,    thio-C₁₋₈alkyl, substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl,    aryloxy, aryl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy,    aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryl, heteroaryloxy,    heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,    benzofused-heterocyclyl or heterocyclyl,-   wherein phosphonic acid is substituted on the phosphorous atom with    two substituents selected from hydroxy or C₁₋₈alkoxy,-   wherein aryl, aryl-amino, aryloxy, aryl-C₁₋₈alkyl and    aryl-C₁₋₈alkoxy is each optionally substituted on aryl with one,    two, three, four or five substituents each selected from cyano,    halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with one or two oxo substituents, and-   wherein heteroaryl, heteroaryl-amino-sulfonyl and heteroaryloxy is    each optionally substituted on heteroaryl with one, two, three, four    or five substituents each selected from C₁₋₈alkyl, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl or C₁₋₈alkoxycarbonyl.

The present invention is further directed to a compound of formula (Ib):

and forms thereof, wherein

-   L is selected from a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl;-   -X-Y-Z- is a moiety selected from —N(R₃)—N═C(R₃)—, ═N—N(R₃)—C(R₃)═,    —N(R₃)—C(R₃)═C(R₃)—, —C(R₃)₂—C(R₃)₂—C(R₃)₂—, —O—C(R₃)₂—O—,    —N(R₃)—C(R₃)═N—, —O—C(R₃)═C(R₃)—, —N(R₃)—C(R₃)₂—C(R₃)₂— or    —S—C(R₃)═N—; wherein the dashed lines in formula (Ib) represent the    locations for one or two double bonds when present in the moiety;-   R₁ is selected from hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl, C₁₋₈alkoxy,    C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl,    C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,    aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,    heterocyclyl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl    or heteroaryl-C₁₋₈alkyl,-   wherein aryl-C₁₋₈alkyl is optionally substituted on aryl with one,    two, three, four or five substituents each selected from hydroxy,    C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino or C₁₋₈alkoxycarbonyl,    and-   wherein heterocyclyl-C₁₋₈alkyl is optionally substituted on    heterocyclyl with one, two, three or four substituents each selected    from hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino or    C₁₋₈alkoxycarbonyl;-   R₂ is selected from hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and-   R₃ is selected from hydrogen, halogen, hydroxy, C₁₋₈alkyl,    C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl,    hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl, amino,    C₁₋₈alkyl-amino, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,    C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,    carboxy, C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl,    thio-C₁₋₈alkyl, substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl,    aryloxy, aryl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy,    aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryl, heteroaryloxy,    heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,    benzofused-heterocyclyl or heterocyclyl,-   wherein phosphonic acid is substituted on the phosphorous atom with    two substituents selected from hydroxy or C₁₋₈alkoxy,-   wherein aryl, aryl-amino, aryloxy, aryl-C₁₋₈alkyl and    aryl-C₁₋₈alkoxy is each optionally substituted on aryl with one,    two, three, four or five substituents each selected from cyano,    halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with one or two oxo substituents, and-   wherein heteroaryl, heteroaryl-amino-sulfonyl and heteroaryloxy is    each optionally substituted on heteroaryl with one, two, three, four    or five substituents each selected from C₁₋₈alkyl, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl or C₁₋₈alkoxycarbonyl.

The present invention is further directed to a compound of formula (Ic):

and forms thereof, wherein

-   L is selected from a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl;-   Ar is selected from aryl, heteroaryl, benzofused-heterocyclyl or    benzofused-C₃₋₁₂cycloalkyl;-   R₂ is selected from hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and-   R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen, halogen,    hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,    hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,    C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,    carboxy, C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl,    thio-C₁₋₈alkyl, substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl,    aryloxy, aryl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy,    aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryl, heteroaryloxy,    heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,    benzofused-heterocyclyl or heterocyclyl,-   wherein phosphonic acid is substituted on the phosphorous atom with    two substituents selected from hydroxy or C₁₋₈alkoxy,-   wherein aryl, aryloxy, aryl-amino, aryl-C₁₋₈alkyl and    aryl-C₁₋₈alkoxy is each optionally substituted on aryl with one,    two, three, four or five substituents each selected from cyano,    halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with one or two oxo substituents, and-   wherein heteroaryl, heteroaryl-amino-sulfonyl and heteroaryloxy is    each optionally substituted on heteroaryl with one, two, three, four    or five substituents each selected from C₁₋₈alkyl, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl or C₁₋₈alkoxycarbonyl.

An example of a compound of formula (Ic) and forms thereof includes acompound wherein R₂ is selected from hydrogen.

An example of a compound of formula (Ic) and forms thereof includes acompound wherein R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen,halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy,cyano-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl, carboxy,C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl,substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl, aryloxy, aryl-amino,aryl-C₁₋₈ alkyl, aryl-C₁₋₈alkoxy, aryl-carbonyl-C₁₋₈alkyl, aryl-amido,heteroaryl, heteroaryloxy, heteroaryl-C₁₋₈alkoxy,heteroaryl-amino-sulfonyl, benzofused-heterocyclyl or heterocyclyl,wherein phosphonic acid is substituted on the phosphorous atom with twoC₁₋₈alkoxy substituents,

-   wherein aryl, aryl-amino, aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy is each    optionally substituted on aryl with one or two substituents each    selected from cyano, halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino,    C₁₋₈alkyl-amino, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl or    C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with two oxo substituents, and-   wherein heteroaryl-amino-sulfonyl and heteroaryloxy is each    optionally substituted on heteroaryl with one or two C₁₋₈alkyl    substituents.

An example of a compound of formula (Ic) and forms thereof includes acompound wherein R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen,halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy,cyano-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl, carboxy,C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl,substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl, aryloxy, aryl-amino,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy, aryl-carbonyl-C₁₋₈alkyl, aryl-amido,heteroaryl, heteroaryloxy, heteroaryl-C₁₋₈alkoxy,heteroaryl-amino-sulfonyl, benzofused-heterocyclyl or heterocyclyl,

-   wherein phosphonic acid is substituted on the phosphorous atom with    two C₁₋₈alkoxy substituents,-   wherein aryl, aryl-amino, aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy is each    optionally substituted on aryl with one or two substituents each    selected from cyano, halogen, C₁₋₈alkoxy or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with two oxo substituents, and-   wherein heteroaryl-amino-sulfonyl and heteroaryloxy is each    optionally substituted on heteroaryl with one or two C₁₋₈alkyl    substituents.

An example of a compound of formula (Ic) and forms thereof includes acompound wherein R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen,halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkyl,halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl, C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl, C₁₋₈alkoxy-imino-C₁₋₈alkyl,C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl, C₁₋₈acyl, C₁₋₈acyl-amino,C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl, substituted phosphonic acid,C₃₋₁₂cycloalkyl, aryl, aryloxy, aryl-amino, aryl-C₁₋₈alkyl,aryl-C₁₋₈alkoxy, aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryloxy,heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,benzofused-heterocyclyl or heterocyclyl,

-   wherein phosphonic acid is substituted on the phosphorous atom with    two C₁₋₈alkoxy substituents,-   wherein aryl, aryl-amino, aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy is each    optionally substituted on aryl with one or two substituents each    selected from cyano, halogen, C₁₋₈alkoxy or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with two oxo substituents, and-   wherein heteroaryl-amino-sulfonyl and heteroaryloxy is each    optionally substituted on heteroaryl with one or two C₁₋₈alkyl    substituents.

An example of a compound of formula (Ic) and forms thereof includes acompound wherein

-   L is selected from a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl;-   Ar is selected from aryl, heteroaryl, benzofused-heterocyclyl or    benzofused-C₃₋₁₂cycloalkyl;-   R₂ is selected from hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and-   R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen, halogen,    hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkyl, halo-C₁₋₈alkoxy,    cyano-C₁₋₈alkyl, C₁₋₈alkyl-amino,    C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,    C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,    C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl,    substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl, aryloxy,    aryl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy,    aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryloxy,    heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,    benzofused-heterocyclyl or heterocyclyl,-   wherein phosphonic acid is substituted on the phosphorous atom with    two C₁₋₈alkoxy substituents,-   wherein aryl, aryl-amino, aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy is each    optionally substituted on aryl with one or two substituents each    selected from cyano, halogen, C₁₋₈alkoxy or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with two oxo substituents, and-   wherein heteroaryl-amino-sulfonyl and heteroaryloxy is each    optionally substituted on heteroaryl with one or two C₁₋₈alkyl    substituents.

The present invention is further directed to a compound of formula (Id):

and forms thereof, wherein

-   L is selected from a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl;-   R₂ is selected from hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and-   R₃, R₄, R₅, R₆ and R₇ is each selected from hydrogen, halogen,    hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,    hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,    C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,    carboxy, C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl,    thio-C₁₋₈alkyl, substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl,    aryloxy, aryl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy,    aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryl, heteroaryloxy,    heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,    benzofused-heterocyclyl or heterocyclyl,-   wherein phosphonic acid is substituted on the phosphorous atom with    two substituents selected from hydroxy or C₁₋₈alkoxy,-   wherein aryl, aryl-amino, aryloxy, aryl-C₁₋₈alkyl and    aryl-C₁₋₈alkoxy is each optionally substituted on aryl with one,    two, three, four or five substituents each selected from cyano,    halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with one or two oxo substituents, and-   wherein heteroaryl, heteroaryl-amino-sulfonyl and heteroaryloxy is    each optionally substituted on heteroaryl with one, two, three, four    or five substituents each selected from C₁₋₈alkyl, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl or C₁₋₈alkoxycarbonyl.

The present invention is further directed to a compound of formula (Ie):

and forms thereof, wherein

-   L is selected from a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl;-   -X-Y-Z- is a moiety selected from —N(R₃)—N═C(R₃)—, ═N—N(R₃)—C(R₃)═,    —N(R₃)—C(R₃)═C(R₃)—, —C(R₃)₂—C(R₃)₂—C(R₃)₂—, —O—C(R₃)₂—O—,    —N(R₃)—C(R₃)═N—, —O—C(R₃)═C(R₃)—, —N(R₃)—C(R₃)₂—C(R₃)₂— or    —S—C(R₃)═N—; wherein the dashed lines in formula (Ie) represent the    locations for one or two double bonds when present in the moiety;-   R₂ is selected from hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and-   R₃ is selected from hydrogen, halogen, hydroxy, C₁₋₈alkyl,    C₁₋₈alkoxy,-   C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl,    hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl, amino,    C₁₋₈alkyl-amino, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,    C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,    carboxy, C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl,    thio-C₁₋₈alkyl, substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl,    aryloxy, aryl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy,    aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryl, heteroaryloxy,    heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,    benzofused-heterocyclyl or heterocyclyl,-   wherein phosphonic acid is substituted on the phosphorous atom with    two substituents selected from hydroxy or C₁₋₈alkoxy,-   wherein aryl, aryl-amino, aryloxy, aryl-C₁₋₈alkyl and    aryl-C₁₋₈alkoxy is each optionally substituted on aryl with one,    two, three, four or five substituents each selected from cyano,    halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with one or two oxo substituents, and-   wherein heteroaryl, heteroaryl-amino-sulfonyl and heteroaryloxy is    each optionally substituted on heteroaryl with one, two, three, four    or five substituents each selected from C₁₋₈alkyl, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl or C₁₋₈alkoxycarbonyl.

The present invention is further directed to a compound of formula (If):

and forms thereof, wherein

-   X₁ and X₂ is each selected from —C(R₆)— or —N—, wherein X₁ and X₂    are not the same;-   L is selected from a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl;-   R₁ is selected from hydrogen, C₁₋₈alkyl, C₁₋₈alkenyl, C₁₋₈alkoxy,    C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,    C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl,    C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,    aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,    heterocyclyl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl    or heteroaryl-C₁₋₈alkyl, wherein aryl-C₁₋₈alkyl is optionally    substituted on aryl with one, two, three, four or five substituents    each selected from hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino,    C₁₋₈alkyl-amino or C₁₋₈alkoxycarbonyl, and wherein    heterocyclyl-C₁₋₈alkyl is optionally substituted on heterocyclyl    with one, two, three or four substituents each selected from    hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino or    C₁₋₈alkoxycarbonyl;-   R₂ is selected from hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and-   R₃, R₄, and R₅ is each selected from hydrogen, halogen, hydroxy,    C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl,    halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy,    cyano-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,    C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,    carboxy, C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈alkoxycarbonyl,    thio-C₁₋₈alkyl, substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl,    aryloxy, aryl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy,    aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryl, heteroaryloxy,    heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,    benzofused-heterocyclyl or heterocyclyl,-   wherein phosphonic acid is substituted on the phosphorous atom with    two substituents selected from hydroxy or C₁₋₈alkoxy,-   wherein aryl, aryl-amino, aryloxy, aryl-C₁₋₈alkyl and    aryl-C₁₋₈alkoxy is each optionally substituted on aryl with one,    two, three, four or five substituents each selected from cyano,    halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,    amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl or C₁₋₈alkoxycarbonyl,-   wherein benzofused-heterocyclyl is optionally substituted on the    heterocyclyl portion with one or two oxo substituents, and-   wherein heteroaryl, heteroaryl-amino-sulfonyl and heteroaryloxy is    each optionally substituted on heteroaryl with one, two, three, four    or five substituents each selected from C₁₋₈alkyl, amino-C₁₋₈alkyl,    C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl or C₁₋₈alkoxycarbonyl;    and-   R₆ is selected from hydrogen, halogen, hydroxy, C₁₋₈alkyl,    C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl,    hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl, amino,    C₁₋₈alkyl-amino, amino-C₁₋₈alkyl or C₁₋₈alkyl-amino-C₁₋₈alkyl.

An example of a compound of Formula (I) includes a compound and formsthereof, wherein (*)-R_(A), R₂, R₃, R₄, R₅, R₆, R₇, L and Ar aredependently selected from (wherein * represents the configuration of theoxime portion in relationship to the double bond; further, when one ormore of R₃, R₄, R₅, R₆ or R₇ is hydrogen, the hydrogen is omitted fromthe following table):

Cpd (*)-R_(A) R₂ L (R₃—R₄—R₅—R₆—R₇)Ar 1 (E)-CH═N—OCH₃ H bond(3-Cl-4-F)phenyl 2 (E)-CH═N—OCH₃ H bond 1-(3-F-benzyl)indazol-5-yl 3(E)-CH═N—OCH₃ H bond (3-Cl-4-F)benzyl 4 (E)-CH═N—OCH₃ H bond[3-Cl-4-(3-F-benzyloxy)]phenyl 5 (E)-CH═N—OCH₃ H bond2-(3-F-benzyl)indazol-5-yl 6 (E)-CH═N—OCH₂C(O)-morpholin-4-yl H bond1-(3-F-benzyl)indazol-5-yl 7 (E)-CH═N—OCH₃ H bond(3-OCH₃-4-phenoxy)phenyl 8 (E)-CH═N—OCH₂C(O)-morpholin-4-yl H bond(3-OCH₃-4-phenoxy)phenyl 9 (E)-CH═N—OCH₃ H bond (3-Cl-4-benzyloxy)phenyl10 (E)-CH═N—OCH₂CH₃ H bond 1-(3-F-benzyl)indazol-5-yl 11(E)-CH═N—OCH₂CH═CH₂ H bond 1-(3-F-benzyl)indazol-5-yl 12(E)-CH═N—O—C(CH₃)₃ H bond 1-(3-F-benzyl)indazol-5-yl 13 (E)-CH═N—OCH₃ Hbond (3-CH₃-4-pyridin-3- yloxy)phenyl 14 (E)-CH═N—OCH₂CH₃ H —CH(R—CH₃)—phenyl 15 (Z)—CH═N—OH H bond 1-(3-F-benzyl)indazol-5-yl 16(E)-CH═N—OCH₂CH₃ H —CH(S—CH₃)— phenyl 17 (E)-CH═N—OCH₂CH₃ H bondindol-5-yl 18 (E)-CH═N—OCH₂CH₃ H bond [3-Cl-4-(3-F-benzyloxy)]phenyl 19(E)-CH═N—O(CH₂)₂-morpholin-4-yl H bond 1-(3-F-benzyl)indazol-5-yl 20(E)-CH═N—OCH₃ H bond indan-5-yl 21 (E)-CH═N—OCH₃ H bond 4-OCHF₂-phenyl22 (E)-CH═N—OCH₃ H bond indazol-5-yl 23 (E)-CH═N—OCH₃ H bondbenzo[1,3]dioxol-5-yl 24 (E)-CH═N—OCH₃ H bond (4-phenoxy)phenyl 25(E)-CH═N—OCH₃ H bond (4-benzyloxy)phenyl 26 (E)-CH═N—OCH₃ H bond4-CH(CH₃)CH₂CH₃-phenyl 27 (E)-CH═N—OCH₃ H bond 4-C(CH₃)₃-phenyl 28(E)-CH═N—OCH₃ H bond (3-benzyloxy)phenyl 29 (E)-CH═N—OCH₃ H bond[3-CH₃-4-(6-CH₃-pyridin-3- yloxy)]phenyl 30 (E)-CH═N—OCH₂CH(CH₃)₂ H bond1-(3-F-benzyl)indazol-5-yl 31 (E)-CH═N—O(CH₂)₂-phenoxy H bond1-(3-F-benzyl)indazol-5-yl 32 (E)-CH═N—OCH₃ H bond(3-Cl-4-pyridin-2-yloxy)phenyl 33 (E)-CH═N—OCH₂CH₃ H bond1-(3-F-benzyl)indol-5-yl 34 (E)-CH═N—OCH₃ H bond1-(3-F-benzyl)indol-5-yl 35 (E)-CH═N—OCH₃ H —CH₂CF₂— 6-CH₃-pyridin-2-yl36 (E)-CH═N—OCH₃ H bond 3-Br-phenyl 37 (E)-CH═N—OCH₂CH₃ H bond(3-Cl-4-benzyloxy)phenyl 38 (E)-CH═N—OCH₃ H bond(3-Cl-4-pyridin-3-yloxy)phenyl 39 (E)-CH═N—OCH₃ CH₃ bond[3-Cl-4-(3-F-benzyloxy)]phenyl 40 (E)-CH═N—OCH₃ CH₂CH₃ bond1-(3-F-benzyl)indazol-5-yl 41 (E)-CH═N—OCH₂CH₃ CH₂CH₃ bond1-(3-F-benzyl)indazol-5-yl 42 (E)-CH═N—OCH₃ CH₂CH₃ bond[3-Cl-4-(3-F-benzyloxy)]phenyl 43 (E)-CH═N—OCH₂CH₃ CH₂CH₃ bond[3-Cl-4-(3-F-benzyloxy)]phenyl 44 (E)-CH═N—(4-OCH₃-benzyloxy) H bond1-(3-F-benzyl)indazol-5-yl 45 (E)-CH═N—(2-OCH₃-benzyloxy) H bond1-(3-F-benzyl)indazol-5-yl 46 (E)-CH═N—benzyloxy H bond1-(3-F-benzyl)indazol-5-yl 47 (E)-CH═N—OCH(CH₃)₂ H bond1-(3-F-benzyl)indazol-5-yl 48 (E)-CH═N—OCH₃ H bond 1-benzyl-indazol-5-yl49 (E)-CH═N—OCH₂CH₃ H bond 1-benzyl-indazol-5-yl 50 (E)-CH═N—OCH₃ H bond1-(3-CN-benzyl)indazol-5-yl 51 (E)-CH═N—OCH₂CH₃ H bond1-(3-CN-benzyl)indazol-5-yl 52 (E)-CH═N—OCH₂CH₃ H bond2-benzyl-indazol-5-yl 53 (E)-CH═N—OCH₃ CH₃ bond1-(3-F-benzyl)indazol-5-yl 54 (E)-CH═N—OCH₃ H bond1-(3-Cl-benzyl)indazol-5-yl 55 (E)-CH═N—OCH₂CH₃ H bond1-(3-Cl-benzyl)indazol-5-yl 56 (E)-CH═N—OCH₃ H bond1-(3-OCH₃-benzyl)indazol-5-yl 57 (E)-CH═N—OCH₂CH₃ H bond1-(3-OCH₃-benzyl)indazol-5-yl 58 (E)-CH═N—OCH₂CH₃ H bond2-(3-F-benzyl)benzoimidazol-5-yl 59 (E)-CH═N—OCH₃ H bond 3-Cl-phenyl 60(E)-CH═N—OCH₃ H bond 2-(3-F-benzyl)benzoimidazol-5-yl 61 (E)-CH═N—OCH₃ Hbond [3-OCH₃-4-(3-F- benzyloxy)]phenyl 62 (E)-CH═N—OCH₂CH₃ H bond[3-OCH₃-4-(3-F- benzyloxy)]phenyl 63 (E)-CH═N—OCH₃ H bond(3-Cl-4-OCH₃)phenyl 64 (E)-CH═N—OCH₃ H bond(3-Cl-4-morpholin-4-yl)phenyl 65 (E)-CH═N—phenoxy H bond1-(3-F-benzyl)indazol-5-yl 66 (E)-CH═N—OCH₃ H bond1-(4-F-benzyl)indazol-5-yl 67 (E)-CH═N—OCH₂CH₃ H bond1-(4-F-benzyl)indazol-5-yl 68 (E)-CH═N—O(CH₂)₂OCH₃ H bond1-(3-F-benzyl)indazol-5-yl 69 (Z)—CH═N—O(CH₂)₃OH H bond1-(3-F-benzyl)indazol-5-yl 70 (E)-CH═N—O(CH₂)₃N(CH₃)₂ H bond1-(3-F-benzyl)indazol-5-yl 71 (E)-CH═N—O(CH₂)₂OCH₃ H bond(3-Cl-4-benzyloxy)phenyl 72 (E)-CH═N—OCH₃ H bond2-(3-F-phenyl)benzofuran-5-yl 73 (E)-CH═N—OCH₃ H bond2-benzyl-benzofuran-5-yl 74 (E)-CH═N—OCH₃ H bond1-(3-F-benzyl)-2,3-dihydro- indol-5-yl 75 (E)-CH═N—O(CH₂)₃OH H bond[3-Cl-4-(3-F-benzyloxy)]phenyl 76 (E)-CH═N—O(CH₂)₃OH H bond(3-Cl-4-benzyloxy)phenyl 77 (E)-CH═N—OH H bond (3-Cl-4-benzyloxy)phenyl78 (E)-CH═N—O(CH₂)₂-morpholin-4-yl H bond (3-Cl-4-benzyloxy)phenyl 79(E)-CH═N—OH H bond [3-Cl-4-(3-F-benzyloxy)]phenyl 80 (E)-CH═N—OCH₃ Hbond (2-F-4-Cl)phenyl 81 (Z)—CH═N—OCH₃ H bond (2-F-4-Cl)phenyl 82(E)-CH═N—OCH₃ H bond (2-F-4-Br)phenyl 83 (Z)—CH═N—OCH₃ H bond(2-F-4-Br)phenyl 84 (E)—CH═N—OH H bond 1-(3-F-benzyl)indazol-5-yl 85(E)-CH═N—O(CH₂)₃OH H bond 1-(3-F-benzyl)indazol-5-yl 86 (E)-CH═N—OCH₃CH₃ bond (2-F-4-Br)phenyl 87 (E)-CH═N—O(CH₂)₃-morpholin-4-yl H bond1-(3-F-benzyl)indazol-5-yl 88 (E)-CH═N—OH H bond1-(3-F-benzyl)indol-5-yl 89 (E)-CH═N—OCH₃ H bond (4-Cl-2-F-5-OH)phenyl90 (Z)—CH═N—OCH₃ H bond (4-Cl-2-F-5-OH)phenyl 91 (E)-CH═N—O(CH₂)₃OH Hbond 1-(3-F-benzyl)indol-5-yl 92 (E)-CH═N—O(CH₂)₃-piperidin-1-yl H bond1-(3-F-benzyl)indazol-5-yl 93 (E)-CH═N—O(CH₂)₂-morpholin-4-yl H bond[3-Cl-4-(3-F-benzyloxy)]phenyl 94 (E)-CH═N—O(CH₂)₂-piperidin-1-yl H bond[3-Cl-4-(3-F-benzyloxy)]phenyl 95 (E)-CH═N—O(CH₂)₂-piperidin-1-yl H bond(3-Cl-4-benzyloxy)phenyl 96 (E)-CH═N—O(CH₂)₂-piperidin-1-yl H bond[1-(3-F-benzyl)]indazol-5-yl 97 (E)-CH═N—OCH₃ H bond [3-Cl-4-(3,5-F₂-benzyloxy)]phenyl 98 (E)-CH═N—OH H bond [3-Cl-4-(3,5-F₂-benzyloxy)]phenyl 99 (E)-CH═N—O(CH₂)₂-morpholin-4-yl H bond[3-Cl-4-(3,5-F₂- benzyloxy)]phenyl 100 (E)-CH═N—OH H —CH(S—CH₃)— phenyl101 (E)-CH═N—O(CH₂)₂-morpholin-4-yl H bond 1-(3-F-benzyl)indol-5-yl 102(E)-CH═N—O(CH₂)₂-piperidin-1-yl H bond 1-(3-F-benzyl)indol-5-yl 103(E)-CH═N—O(CH₂)₂-morpholin-4-yl H —CH(S—CH₃)— phenyl 104 (E)-CH═N—OCH₃ Hbond [4-NHC(O)-phenyl]phenyl 105 (E)-CH═N—OH H bond[4-NHC(O)-phenyl]phenyl 106 (E)-CH═N—O(CH₂)₂-piperidin-1-yl H—CH(S—CH₃)— phenyl 107 (E)-CH═N—O(CH₂)₂-morpholin-4-yl H bond[4-NHC(O)-phenyl]phenyl 108 (E)-CH═N—O(CH₂)₂-morpholin-4-yl H bond(3-Cl-4-F)phenyl 109 (E)-CH═N—O(CH₂)₂-morpholin-4-yl H bond(4-phenoxy)phenyl 110 (E)-CH═N—OCH₃ H bond[2-NHC(O)-phenyl]pyrimidin-5-yl 111 (E)-CH═N—OH H bond (4-phenoxy)phenyl112 (E)-CH═N—O(CH₂)₃-morpholin-4-yl H bond (3-Cl-4-benzyloxy)phenyl 113(E)-CH═N—O(CH₂)₃O—SO₂CH₃ H bond (3-Cl-4-benzyloxy)phenyl 114(E)-CH═N—OCH₂-pyridin-2-yl H bond (3-Cl-4-benzyloxy)phenyl 115(E)-CH═N—O(CH₂)₃—NH(CH₂)₂—OCH₃ H bond (3-Cl-4-benzyloxy)phenyl 116(E)-CH═N—O(CH₂)₃-(4-OH-piperidin-1-yl) H bond (3-Cl-4-benzyloxy)phenyl117 (E)-CH═N—OCH₂-(1-C(O)O—C(CH₃)₃-piperidin-4-yl) H bond(3-Cl-4-benzyloxy)phenyl 118 CN H bond (3-Cl-4-benzyloxy)phenyl 119(E)-CH═N—CH₂-benzo[1,3]dioxol-5-yl H —CH₂— benzo[1,3]dioxol-5-yl 120(E)-CH═N—OCH₃ H bond (4-OCH₃)phenyl 121 (E)-CH═N—OCH₃ H —CH₂—benzo[1,3]dioxol-5-yl 122 (E)-CH═N—OCH₃ H bond [3,4-OCH₃)₂]benzyl 123(E)-CH═N—OCH₃ H bond (4-phenoxy)benzyl 124 (E)-CH═N—OCH₃ H bond(1R)-indan-1-yl 125 (E)-CH═N—OCH₃ H bond1,2,3,4-tetrahydro-naphthalen-1-yl 126 (E)-CH═N—OCH₃ H —CH(CH₃)—(4-Cl)phenyl 127 (E)-CH═N—OCH₃ H —CH[(S)—CH₃)]— (4-OCH₃)phenyl 128(E)-CH═N—OCH₃ H bond (2-phenoxy)pyridin-5-yl 129 (E)-CH═N—OCH₃ H bond(2-morpholin-4-yl)pyridin-5-yl 130 (E)-CH═N—OCH₃ H bond1,4-dioxo-1,2,3,4-tetrahydro- phthalazin-5-yl 131 (E)-CH═N—OCH₃ H bond(2-F-5-CH₃)phenyl 132 (E)-CH═N—OCH₃ H bond [2,4,6-(CH₃)₃]phenyl 133(E)-CH═N—OCH₃ H bond (2-CH₃-3-Cl)phenyl 134 (E)-CH═N—OCH₃ H bond(3-SCH₃)phenyl 135 (E)-CH═N—OCH₃ H bond [3-C(CH₃)═N(OCH₃)]phenyl 136(E)-CH═N—OCH₃ H bond [3,5-(CH₃)₂]phenyl 137 (E)-CH═N—OCH₃ H bond[4-NHC(O)CH₃]phenyl 138 (E)-CH═N—OCH₃ H bond phenyl 139 (E)-CH═N—OCH₃ Hbond (4-morpholin-4-yl)phenyl 140 (E)-CH═N—OCH₃ H bond (2-CH₃)phenyl 141(E)-CH═N—OCH₃ H bond (3,4-F₂)phenyl 142 (E)-CH═N—OCH₃ H bond(3-F-4-CH₃)phenyl 143 (E)-CH═N—OCH₃ H bond (3,4-Cl₂)phenyl 144(E)-CH═N—OCH₃ H bond (3-Cl-4-CH₃)phenyl 145 (E)-CH═N—OCH₃ H bond{2-CH₃-4-[CH₂C(O)-phenyl]-5- Cl}phenyl 146 (E)-CH═N—OCH₃ H bond(3-CH₂CH₃)phenyl 147 (E)-CH═N—OCH₃ H bond [4-CH(CH₃)₂]phenyl 148(E)-CH═N—OCH₃ H bond indazol-5-yl 149 (E)-CH═N—OCH₃ H bond (3-CF₃)phenyl150 (E)-CH═N—OCH₃ H bond (3-CH₃)phenyl 151 (E)-CH═N—OCH₃ H bond(4-Cl)phenyl 152 (E)-CH═N—OCH₃ H bond (2-CH₃-4-Cl)phenyl 153(E)-CH═N—OCH₃ H bond (4-NH-phenyl)phenyl 154 (E)-CH═N—OCH₃ H bond[4-N(CH₂CH₃)₂]phenyl 155 (E)-CH═N—OCH₃ H bond [4-C(O)OCH₃]phenyl 156(E)-CH═N—OCH₃ H bond [4-C(phenyl)═N(OCH₃)]phenyl 157 (E)-CH═N—OCH₃ Hbond [4-C(O)CH₃]phenyl 158 (E)-CH═N—OCH₃ H bond [4-C(CH₃)═N(OCH₃)]phenyl159 (E)-CH═N—OCH₃ H bond (4-CH₂CN)phenyl 160 (E)-CH═N—OCH₃ H bond[2-OCH₃-4-(NH-phenyl)]phenyl 161 (E)-CH═N—OCH₃ H bond[2-OCH₃-4-NHC(O)CH₃]phenyl 162 (E)-CH═N—OCH₃ H bond (4-cyclohexyl)phenyl163 (E)-CH═N—OCH₃ H bond naphthalen-1-yl 164 (E)-CH═N—OCH₃ H bond(4-Cl)naphthalen-1-yl 165 (E)-CH═N—OCH₃ H bond (2,4-F₂)phenyl 166(E)-CH═N—OCH₃ H bond (2-SCH₃)phenyl 167 (E)-CH═N—OCH₃ H bond (3-F)phenyl168 (E)-CH═N—OCH₃ H bond (2-CH₃-5-F)phenyl 169 (E)-CH═N—OCH₃ H bond(3,5-Cl₂)phenyl 170 (E)-CH═N—OCH₃ H bond (2-OCH₃-5-Cl)phenyl 171(E)-CH═N—OCH₃ H bond (2-CH₃-5-Cl)phenyl 172 (E)-CH═N—OCH₃ H bond(4-F)phenyl 173 (E)-CH═N—OCH₃ H bond biphenyl 174 (E)-CH═N—OCH₃ H bond(4-SCH₃)phenyl 175 (E)-CH═N—OCH₃ H bond [3,5-(OCH₃)₂]phenyl 176(E)-CH═N—OCH₃ H bond [3,4,5-(OCH₃)₃]phenyl 177 (E)-CH═N—OCH₃ H bond[3,4-(OCH₃)₂]phenyl 178 (E)-CH═N—OCH₃ H bond5,6,7,8-tetrahydro-naphthalen-1-yl 179 (E)-CH═N—OCH₃ H bond(4-SO₂NH-pyrimidin-2- yl)phenyl 180 (E)-CH═N—OCH₃ H bond[3-C(O)OCH₂CH₃]phenyl 181 (E)-CH═N—OCH₃ H bond[4-CH₂P(═O)—(OCH₂CH₃)₂]phenyl 182 (E)-CH═N—OCH₃ H bond (4-CH₂CH₃)phenyl183 (E)-CH═N—OCH₃ H bond (4-{SO₂NH-[3,5-(CH₃)₂- pyrazin-2-yl]})phenyl184 (E)-CH═N—OCH₃ H bond (2-CH₃)benzothiazol-5-yl 185 (E)-CH═N—OCH₃ Hbond [4-NH-(4-OCH₃-phenyl)]phenyl 186 (E)-CH═N—OCH₃ H bond[4-N(CH₃)₂]phenyl 187 (E)-CH═N—OCH₃ H bond[4-C(O)NH(CH₂)₂—N(CH₂CH₃)₂]phenyl 188 (E)-CH═N—OCH₃ H bond[4-C(O)O(CH₂)₃CH₃]phenyl 189 (E)-CH═N—OCH₃ H bond indan-4-yl 190(E)-CH═N—OCH₃ H bond (4′-Cl)biphenyl 191 (E)-CH═N—OCH₃ H bond[2-(4-F-phenoxy)]pyridin-5-yl 192 (E)-CH═N—OCH₃ H bond[4′-C(O)OCH₃]biphenyl 193[5-(CH₂)₂-morpholin-4-yl]-[1,3,4]oxadiazol-2-yl H bond(3-Cl-4-benzyloxy)phenyl

Examples of a compound of Formula (I) include compounds selected fromthe group consisting of:

Chemical Definitions & Nomenclature

Bond lines drawn into a ring system from a substituent variable indicatethat the substituent may be attached to any of the substitutable ringatoms.

As used herein, the following terms are intended to have the followingdefinitions. The definitions herein may specify that a chemical term hasan indicated formula. The particular formula provided is not intended tolimit the scope of the invention, but is provided as an illustration ofthe term. The scope of the per se definition of the term is intended toinclude the plurality of variations expected to be included by one ofordinary skill in the art. Chemical terms are to be read from right toleft, wherein the right-most group is attached to the core molecule andthe left-most group is the terminal group. The formula (s) illustratinga term are to be read from left to right, wherein the left-most group isattached to the core molecule, as indicated by the dash, and theright-most group is the terminal group.

The term “C₁₋₈alkyl” means a saturated aliphatic branched orstraight-chain hydrocarbon radical or linking group having from 1 up to8 carbon atoms in a linear or branched arrangement, wherein the radicalis derived by the removal of one hydrogen atom from a carbon atom andthe linking group is derived by the removal of one hydrogen atom fromeach of two carbon atoms in the chain. The term “C₁₋₈alkyl” alsoincludes a “C₁₋₆alkyl” and “C₁₋₄alkyl” radical or linking group havingfrom 1 up to 6 carbon atoms and 1 up to 4 carbon atoms respectively,such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl,1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl,2-heptyl, 3-heptyl, 1-octyl, 2-octyl, 3-octyl and the like. Alkylradicals may be attached to a core molecule via a terminal carbon atomor via a carbon atom within the chain. Similarly, substituent variablesmay be attached to an alkyl linking group when allowed by availablevalences.

The term “C₂₋₈alkenyl” means an alkyl radical or linking group havingfrom 2 up to 8 carbon atoms in a linear or branched arrangement havingat least one carbon-carbon double bond. The term “C₂₋₈alkenyl” alsoincludes a “C₂₋₄alkenyl” radical or linking group having from 2 up to 4carbon atoms, such as ethenyl (also referred to as vinyl), iso-propenyl,allyl (also referred to as propenyl), propylidene and the like.

The term “C₁₋₈alkoxy” means an alkyl radical or linking group havingfrom 1 up to 8 carbon atoms in a linear or branched arrangement, whereinthe radical or linking group is attached through an oxygen linking atom,as in the formula: —O—C₁₋₈alkyl. The term “C₁₋₈alkoxy” also includes a“C₁₋₆alkoxy” and “C₁₋₄alkoxy” radical or linking group having from 1 upto 6 carbon atoms and from 1 up to 4 carbon atoms respectively, such asmethoxy, ethoxy, propoxy, butoxy and the like. An alkoxy radical may beattached to a core molecule and further substituted as a linking groupwhere indicated.

The term “C₃₋₁₂cycloalkyl” means a saturated or partially unsaturatedcyclic hydrocarbon ring system radical. The term “C₃₋₁₂cycloalkyl” alsoincludes a C₃₋₈cycloalkyl, C₃₋₁₀cycloalkyl, C₅₋₆cycloalkyl,C₅₋₈cycloalkyl, C₅₋₁₂cycloalkyl, C₉₋₁₃cycloalkyl orbenzofused-C₃₋₁₂cycloalkyl ring system radical and the like, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, 1H-indenyl, indanyl, 9H-fluorenyl,1,2,3,4-tetrahydro-naphthalenyl, acenaphthenyl, adamantanyl and thelike.

The term “benzofused-C₃₋₁₂cycloalkyl” means a C₃₋₁₂cycloalkyl ringsystem radical having a benzene ring fused on the ring system onadjacent carbons. Examples of benzofused-C₃₋₁₂cycloalkyl in compoundsrepresentative of the present invention include abenzofused-C₅₋₆cycloalkyl ring system radical and the like, such as1H-indenyl, indanyl and the like.

The term “aryl” means an unsaturated aromatic hydrocarbon ring systemradical. Aryl ring systems include phenyl, naphthalenyl, azulenyl,anthracenyl and the like. Examples of aryl in compounds representativeof the present invention include phenyl or naphthalenyl.

The term “hetero”, when used as a prefix for a ring system, refers tothe replacement of at least one carbon atom member in the ring systemwith a heteroatom selected from N, O, S, S(O), or SO₂. A hetero ring mayhave 1, 2, 3 or 4 carbon atom members replaced by a nitrogen atom.Alternatively, a ring may have 1, 2 or 3 nitrogen atom members and 1oxygen or sulfur atom member. Alternatively, a ring may have 1 oxygen orsulfur atom member. Alternatively, up to two adjacent ring members maybe heteroatoms, wherein one heteroatom is nitrogen and the otherheteroatom is selected from N, S or O.

The term “heterocyclyl” means a saturated or partially unsaturated“hetero” ring system radical. Heterocyclyl ring systems includeazetidinyl, 2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl,1,3-dioxolanyl, 2-imidazolinyl (also referred to as4,5-dihydro-1H-imidazolyl), imidazolidinyl, 2-pyrazolinyl,pyrazolidinyl, tetrazolyl, tetrazolidinyl, piperidinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, azepanyl,hexahydro-1,4-diazepinyl, hexahydro-1,4-oxazepanyl, tetrahydro-furanyl,tetrahydro-thienyl, tetrahydro-pyranyl, tetrahydro-pyridazinyl and thelike. The term “heterocyclyl” also includes a benzofused-heterocyclylring system radical and the like, such as indolinyl (also referred to as2,3-dihydro-indolyl), benzo[1,3]dioxolyl, 2,3-dihydro-1,4-benzodioxinyl,2,3-dihydro-benzofuranyl, 1,2-dihydro-phthalazinyl and the like.

The term “benzofused-heterocyclyl” means a heterocyclyl ring systemradical having a benzene ring fused on the ring system on adjacentcarbons. Examples of benzofused-heterocyclyl in compounds representativeof the present invention include benzo[1,3]dioxolyl and2,3-dihydro-indolyl.

The term “heteroaryl” means a monovalent, unsaturated aromatic “hetero”ring system radical. Heteroaryl ring systems include furyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl and the like.

The term “heteroaryl” also includes a benzofused-heteroaryl ring systemradical and the like, such as indolizinyl, indolyl, azaindolyl,isoindolyl, benzofuranyl, benzothienyl, indazolyl, azaindazolyl,benzoimidazolyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl,benzothiadiazolyl, benzotriazolyl, purinyl, 4H-quinolizinyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,1,8-naphthyridinyl, pteridinyl and the like.

The term “benzofused-heteroaryl” means a heteroaryl ring system radicalhaving a benzene ring fused on the ring system on adjacent carbons.Examples of benzofused-heteroaryl in compounds representative of thepresent invention include indazolyl, indolyl, benzofuranyl andbenzoimidazolyl.

The term “C₁₋₈acyl” means a radical of the formula: —C(O)H or—C(O)—C₁₋₈alkyl, or a linking group of the formula:—C(O)—C₁₋₈alkyl-terminal group.

The term “C₁₋₈acyl-amino” means a radical of the formula: —NH—C(O)H or—NH—C(O)—C₁₋₈alkyl, or a linking group of the formula:—NH—C(O)—C₁₋₈alkyl-terminal group.

The term “C₁₋₈alkoxy-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl-O—C₁₋₈alkyl, or a linking group of the formula:—C₁₋₈alkyl-O—C₁₋₈alkyl-terminal group.

The term “C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl” means a radical of theformula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-O—C₁₋₈alkyl,—C₁₋₈alkyl-N[(C₁₋₈alkyl)(C₁₋₈alkyl-O—C₁₋₈alkyl)] or—C₁₋₈alkyl-N(C₁₋₈alkyl-O—C₁₋₈alkyl)₂, or a linking group of the formula:—C₁₋₈alkyl-NH—C₁₋₈alkyl-O—C₁₋₈alkyl-terminal group,—C₁₋₈alkyl-N[(C₁₋₈alkyl)(C₁₋₈alkyl-O—C₁₋₈alkyl-terminal group)],—C₁₋₈alkyl-N[(C₁₋₈alkyl-terminal group)(C₁₋₈alkyl-O—C₁₋₈alkyl)] or—C₁₋₈alkyl-N[(C₁₋₈alkyl)(C₁₋₈alkyl-O—C₁₋₈alkyl-terminal group)].

The term “C₁₋₈alkoxycarbonyl” means a radical of the formula:—C(O)—O—C₁₋₈alkyl, or a linking group of the formula:—C(O)—O—C₁₋₈alkyl-terminal group.

The term “C₁₋₈alkoxy-imino-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl=N(C₁₋₈alkoxy).

The term “C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl” means a radical of theformula: —C₁₋₈alkyl(aryl)=N(C₁₋₈alkoxy); wherein the aryl and iminoportion is substituted on the same or different C₁₋₈alkyl carbon atom.

The term “C₁₋₈alkyl-amino” means a radical of the formula: —NH—C₁₋₈alkylor —N(C₁₋₈alkyl)₂.

The term “C₁₋₈alkyl-amino-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl-NH—C₁₋₈alkyl or —C₁₋₈alkyl-N(C₁₋₈alkyl)₂, or a linking groupof the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-terminal group or—C₁₋₈alkyl-N(C₁₋₈alkyl)-C₁₋₈alkyl-terminal group.

The term “C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl” means a radical ofthe formula: —C(O)—NH—C₁₋₈alkyl-NH—C₁₋₈alkyl or—C(O)—NH—C₁₋₈alkyl-N(C₁₋₈alkyl)₂.

The term “C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl-SO₂—C₁₋₈alkyl, or a linking group of the formula:—C₁₋₈alkyl-SO₂—C₁₋₈alkyl-terminal group.

The term “C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl” means a radical of theformula: —C₁₋₈alkyl-O—SO₂—C₁₋₈alkyl, or a linking group of the formula:—C₁₋₈alkyl-O—SO₂—C₁₋₈alkyl-terminal group.

The term “amino” means a radical of the formula: —NH₂.

The term “amino-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl-NH₂, or a linking group of the formula:—C₁₋₈alkyl-NH-terminal group or —C₁₋₈alkyl-N(terminal group)₂.

The term “aryl-amido” means a radical of the formula: —NHC(O)-aryl.

The term “aryl-amino” means a radical of the formula: —NH-aryl.

The term “aryl-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl-aryl.

The term “aryl-carbonyl-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl-C(O)-aryl.

The term “aryl-C₁₋₈alkoxy” means a radical of the formula:—O—C₁₋₈alkyl-aryl.

The term “aryloxy” means a radical of the formula: —O-aryl.

The term “aryloxy-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl-O-aryl.

The term “carboxy” means a radical of the formula: —C(O)OH.

The term “cyano-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl-C≡N.

The term “halogen” or “halo” means the group chloro, bromo, fluoro oriodo.

The term “halo-C₁₋₈alkoxy” means a radical of the formula:—C₁₋₈alkoxy(halo)₁₋₁₇, wherein one or more halogen atoms may besubstituted on C₁₋₈alkoxy when allowed by available valences andincludes monofluoromethoxy, difluoromethoxy, trifluoromethoxy,trifluoroethoxy and the like.

The term “halo-C₁₋₆alkoxy” means a radical of the formula:—C₁₋₆alkoxy(halo)₁₋₁₃, wherein one or more halogen atoms may besubstituted on C₁₋₆alkoxy when allowed by available valences.

The term “halo-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl(halo)₁₋₁₇, wherein one or more halogen atoms may besubstituted on C₁₋₈alkyl when allowed by available valences and includesmonofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl andthe like.

The term “halo-C₁₋₆alkyl” means a radical of the formula:—C₁₋₆alkyl(halo)₁₋₁₃, wherein one or more halogen atoms may besubstituted on C₁₋₆alkyl when allowed by available valences.

The term “heterocyclyl-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl-heterocyclyl.

The term “heterocyclyl-carbonyl-C₁₋₈alkyl” means a radical of theformula: —C₁₋₈alkyl-C(O)-heterocyclyl.

The term “heteroaryl-C₁₋₈alkoxy” means a radical of the formula:—O—C₁₋₈alkyl-heteroaryl.

The term “heteroaryl-C₁₋₈alkyl” means a radical of the formula:—C₁₋₈alkyl-heteroaryl.

The term “heteroaryl-amino-sulfonyl” means a radical of the formula:—SO₂—NH-heteroaryl.

The term “heteroaryloxy” means a radical of the formula: —O-heteroaryl.

The term “hydroxy-C₁₋₈alkoxy” means a radical wherein C₁₋₈alkoxy issubstituted on an available carbon chain atom with one or more hydroxyradicals.

The term “hydroxy-C₁₋₈alkyl” means a radical wherein C₁₋₈alkyl issubstituted on an available carbon chain atom with one or more hydroxyradicals.

The term “substituted phosphonic acid” means a radical of the formula:—P(═O)—(O—C₁₋₈alkyl)₂, —P(═O)—(OH)₂ or —P(═O)(OH)—O—C₁₋₈alkyl.

The term “thio-C₁₋₈alkyl” means a radical of the formula: —S—C₁₋₈alkyl.

The term “substituted” means the independent replacement of one or morehydrogen atoms within a radical with that amount of substituents allowedby available valences.

The term “dependently selected” means that the structure variables arespecified in an indicated combination.

The term “terminal group” means a moiety attached to a linking groupsubstituent at a position other than the point of attachment of thelinking group to the core molecule. The moiety functions to terminatethe structure variable.

In general, IUPAC nomenclature rules are used herein.

Compound Forms

The term “form” means, in reference to compounds of the presentinvention, such may exist as, without limitation, a salt, stereoisomer,tautomer, crystalline, polymorph, amorphous, solvate, hydrate, ester,prodrug or metabolite form. The present invention encompasses all suchcompound forms and mixtures thereof.

The term “isolated form” means, in reference to compounds of the presentinvention, such may exist in an essentially pure state such as, withoutlimitation, an enantiomer, a racemic mixture, a geometric isomer (suchas a cis or trans stereoisomer), a mixture of geometric isomers, and thelike. The present invention encompasses all such compound forms andmixtures thereof.

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the“pharmaceutically acceptable salts” of the compounds of this inventionrefer to non-toxic acidic/anionic or basic/cationic salt forms.

Suitable salt forms include acid addition salts which may, for example,be formed by mixing a solution of the compound according to theinvention with a solution of an acid such as acetic acid, adipic acid,benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid,hydrochloric acid, maleic acid, malonic acid, phosphoric acid,saccharinic acid, succinic acid, sulphuric acid, tartaric acid,trifluoroacetic acid and the like.

Furthermore when the compounds of the present invention carry an acidicmoiety, suitable salts thereof may include alkali metal salts, e.g.sodium or potassium salts; alkaline earth metal salts, e.g. calcium ormagnesium salts; and salts formed with suitable organic ligands, e.g.quaternary ammonium salts.

Thus, representative salts include the following: acetate, adipate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium, camsylate (or camphorsulphonate), carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, fumarate, gluconate,glutamate, glyconate, hydrabamine, hydrobromine, hydrochloride, iodide,isothionate, lactate, malate, maleate, malonate, mandelate, mesylate,nitrate, oleate, pamoate, palmitate, phosphate/diphosphate,saccharinate, salicylate, stearate, sulfate, succinate, tartrate,tosylate, trichloroacetate, trifluoroacetate and the like.

Examples of salt forms of compounds representative of the presentinvention include the monohydrochloride salt.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) Edition, John Wiley & Sons, 1999.The protecting groups may be removed at a convenient subsequent stageusing methods known in the art. The scope of the present inventionencompasses all such protected compound forms and mixtures thereof.

The invention includes compounds of various isomers and mixturesthereof. The term “isomer” refers to compounds that have the samecomposition and molecular weight but differ in physical and/or chemicalproperties. Such substances have the same number and kind of atoms butdiffer in structure. The structural difference may be in constitution(geometric isomers) or in an ability to rotate the plane of polarizedlight (optical isomers).

The term “optical isomer” means isomers of identical constitution thatdiffer only in the spatial arrangement of their groups. Optical isomersrotate the plane of polarized light in different directions. The term“optical activity” means the degree to which an optical isomer rotatesthe plane of polarized light.

The term “racemate” or “racemic mixture” means an equimolar mixture oftwo enantiomeric species, wherein each of isolated specie rotates theplane of polarized light in the opposite direction such that the mixtureis devoid of optical activity.

The term “enantiomer” means an isomer having a nonsuperimposable mirrorimage. The term “diastereomer” means stereoisomers that are notenantiomers.

The term “chiral” means a molecule which, in a given configuration,cannot be superimposed on its mirror image. This is in contrast toachiral molecules which can be superimposed on their mirror images.

The two distinct mirror image versions of the chiral molecule are alsoknown as levo (left-handed), abbreviated L, or dextro (right handed),abbreviated D, depending on which way they rotate polarized light. Thesymbols “R” and “S” represent the configuration of groups around astereogenic carbon atom(s).

An example of an isolated form of an achiral mixture includes adextrorotatory enantiomer, wherein the mixture is substantially free ofthe levorotatory isomer. In this context, substantially free means thelevorotatory isomer may, in a range, comprise less than 25% of themixture, less than 10%, less than 5%, less than 2% or less than 1% ofthe mixture according to the formula:

${\%\mspace{14mu}{levorotatory}} = {\frac{\left( {{mass}\mspace{14mu}{lavorotatory}} \right)}{\left( {{mass}\mspace{14mu}{dextrorotatory}} \right) + \left( {{mass}\mspace{14mu}{levorotatory}} \right)} \times 100}$

Similarly, an example of an isolated form of an achiral mixture includesa levorotatory enantiomer, wherein the mixture is substantially free ofthe dextrorotatory isomer. In this context, substantially free means thedextrorotatory isomer may, in a range, comprise less than 25% of themixture, less than 10%, less than 5%, less than 2% or less than 1% ofthe mixture according to the formula:

${\%\mspace{14mu}{dextrorotatory}} = {\frac{\left( {{mass}\mspace{14mu}{dextrorotatory}} \right)}{\left( {{mass}\mspace{14mu}{dextrorotatory}} \right) + \left( {{mass}\mspace{14mu}{levorotatory}} \right)} \times 100}$

The term “geometric isomer” means isomers that differ in the orientationof substituent atoms in relationship to a carbon-carbon double bond, toa cycloalkyl ring, or to a bridged bicyclic system. Substituent atoms(other than hydrogen) on each side of a carbon-carbon double bond may bein an E or Z configuration. In the “E” configuration, the substituentsare on opposite sides in relationship to the carbon-carbon double bond.In the “Z” configuration, the substituents are oriented on the same sidein relationship to the carbon-carbon double bond.

Substituent atoms (other than hydrogen) attached to a ring system may bein a cis or trans configuration. In the “cis” configuration, thesubstituents are on the same side in relationship to the plane of thering; in the “trans” configuration, the substituents are on oppositesides in relationship to the plane of the ring. Compounds having amixture of “cis” and “trans” species are designated “cis/trans”.

The isomeric descriptors (“R”, “S”, “E”, and “Z”) indicate atomconfigurations and are intended to be used as defined in the literature.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include combining the free base (orfree acid) of each isomer of an isomeric pair using an optically activeacid (or base) to form an optically active salt (followed by fractionalcrystallization and regeneration of the free base), forming an ester oramide of each of the isomers of an isomeric pair by reaction with anappropriate chiral auxiliary (followed by fractional crystallization orchromatographic separation and removal of the chiral auxiliary), orseparating an isomeric mixture of either an intermediate or a finalproduct using various well known chromatographic methods.

Furthermore, compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and, as such, are intended tobe included in the scope of the invention. In addition, some of thecompounds may form solvates with water (i.e., hydrates) or commonorganic solvents (e.g., organic esters such as ethanolate and the like)and, as such, are also intended to be encompassed within the scope ofthis invention.

Methods of Use

The compounds of formula (I) are inhibitors of a protein kinase such asEGFR, HER-1, HER-2 and the like, having an IC₅₀ (50% inhibitionconcentration) or an EC₅₀ (50% effective concentration) in a range ofabout 50 μM or less, of about 25 μM or less, of about 15 μM or less, ofabout 10 μM or less, of about 5 μM or less, of about 1 μM or less, ofabout 0.5 μM or less, of about 0.25 μM or less or of about 0.1 μM orless.

The present invention includes a compound of formula (I) and formsthereof as a protein kinase inhibitor, wherein the protein kinase isselected from EGFR, HER-1 or HER-2.

The present invention includes a prodrug form of a compound of formula(I) and forms thereof as a protein kinase inhibitor.

The present invention includes a metabolite form of a compound offormula (I) and forms thereof as a protein kinase inhibitor.

The present invention includes an isolated form of a compound of formula(I) and forms thereof as a protein kinase inhibitor.

The present invention includes a compound of formula (I) or a formthereof, wherein the compound is labeled with a ligand for use as amarker, and wherein the ligand is a radioligand selected from deuterium,tritium and the like.

The present invention includes use of a compound of formula (I) andforms thereof as an inhibitor of a protein kinase such as EGFR, HER-1,HER-2 and the like comprising contacting the protein kinase domain orreceptor with the compound.

The present invention includes the use of a compound of formula (I) andforms thereof as a pharmaceutical composition, medicine or medicamentfor treating, preventing or ameliorating a kinase mediated disease,disorder or condition.

The present invention includes the use of a compound of formula (I) andforms thereof as a medicament.

The present invention includes the use of a prodrug of a compound offormula (I) and forms thereof as a pharmaceutical composition, medicineor medicament for treating, preventing or ameliorating a kinase mediateddisease, disorder or condition.

The present invention includes the use of a prodrug of a compound offormula (I) and forms thereof as a medicament.

The present invention is directed to a method for treating, preventingor ameliorating a chronic or acute protein kinase mediated disease,disorder or condition in a subject in need thereof comprisingadministering to the subject an effective amount of a compound offormula (I) and forms thereof.

The method of the present invention further comprises administering tothe subject an effective amount of a prodrug of a compound of formula(I) and forms thereof.

The method of the present invention further comprises treating,preventing or ameliorating a chronic or acute EGFR, HER-1 or HER-2mediated disease, disorder or condition.

The method of the present invention wherein the disease, disorder orcondition is associated with increased or unregulated protein kinaseactivity, expression or signaling and the like in the subject.

The method of the present invention further comprises administering tothe subject an effective amount of a compound of formula (I) as apharmaceutical composition, medicine or medicament thereof.

The method of the present invention wherein the disease, disorder orcondition is an EGFR kinase mediated head or brain cancer in thesubject, and wherein the compound penetrates the blood brain barrier.

The method of the present invention further comprises treating orameliorating nerve damage and promoting axon regeneration subsequent toa brain or spinal cord injury in the subject, wherein the compound is anEGFR inhibitor.

The method of the present invention further comprises treating,preventing or ameliorating viral infection by an EGFR kinase mediatedcytomegalovirus in the subject.

The term “chronic or acute protein kinase mediated disease, disorder orcondition” as used herein, includes, and is not limited to diseases,disorders or conditions associated with unregulated kinase activity andconditions that accompany such activity.

The term “unregulated protein kinase activity, expression or signaling”refers to 1) increased or unregulated kinase expression or signaling, 2)increased kinase expression leading to unregulated cell proliferation,3) increased kinase signaling leading to unregulated cell proliferation,or 4) mutations leading to constitutive kinase activation. The existenceof unregulated kinase activity may be determined by procedures wellknown in the art.

The term “unregulated cell proliferation” refers to cell proliferationof one or more subset of cells in a multicellular organism resulting inharm (such as discomfort or decreased life expectancy) to themulticellular organism.

Tumor cells which result from unregulated cell proliferation use manymechanisms to enhance their survival and spread and often have highrates of proliferation because growth control signals that keep normalcells in check are defective. Many tumor cells secrete autocrine growthfactors that increase proliferation rates or they induce other cells tosecrete growth factors that they utilize.

Tumor cells grow and spread by dislodging from a primary tumor site,using proteases to digest the extracellular matrix, spreading inresponse to migration cues, allowing them to migrate to certain tissuespreferentially where overexpressed adhesion molecules allow attachmentand growth at the new site. The totality of these and other biologicalprocesses are responsible for the lethal effects of a tumor. A kinaseinhibitor may affect one or more aspects of tumor survival mechanismsand thus be therapeutically useful. Alternatively, a kinase inhibitormay not affect one particular tumor survival mechanism but may still betherapeutically useful by affecting tumor survival by an unknown or asyet unelucidated mechanism of action.

The foregoing methods contemplate that a compound of formula (I) or aform thereof is useful for treating, preventing or amelioratingdiseases, disorders or conditions such as, without limitation,osteoarthritis, rheumatoid arthritis, synovial pannus invasion inarthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus,diabetic angiopathy, diabetic retinopathy, retinal vessel proliferation,inflammatory bowel disease, Crohn's disease, ulcerative colitis, bonediseases, transplant or bone marrow transplant rejection, lupus, chronicpancreatitis, cachexia, septic shock, fibroproliferative anddifferentiative skin diseases or disorders, central nervous systemdiseases, neurodegenerative diseases, disorders or conditions related tonerve damage and axon degeneration subsequent to a brain or spinal cordinjury, acute or chronic cancer, ocular diseases, viral infections,heart disease, lung or pulmonary diseases or kidney or renal diseases.

Certain diseases, disorders or conditions further include, withoutlimitation, acute or chronic cancer selected from bladder cancer, brain,head or neck cancer, breast cancer, colorectal cancer, endometrialcancer, epidermoid cancer, esophageal cancer, gastric cancer, gliomacancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer,renal cell cancer, Kaposi's sarcoma, leukemia, lymphoma orpapillocarcinoma; and, cancer-associated pathologies selected fromabnormal cell proliferation, unregulated cell proliferation, tumorgrowth, tumor angiopathy, tumor angiogenesis, tumor vascularization ormetastatic cancer cell invasion and migration.

Certain diseases, disorders or conditions further include, withoutlimitation, fibroproliferative and differentiative skin diseases ordisorders selected from papilloma formation, psoriasis, dermatitis,eczema, seborrhea or chemotherapy-induced alopecia; central nervoussystem diseases selected from Alzheimer's disease, Parkinson's diseaseor depression; ocular diseases selected from macular degeneration,diseases of the cornea or glaucoma; viral infections selected frommycotic infection, autoimmune disease or cytomegalovirus; heart diseaseselected from atherosclerosis, neointima formation ortransplantation-induced vasculopathies such as arterial restenosis; lungor pulmonary diseases selected from allergic-asthma, lung fibrosis,pulmonary fibrosis or chronic obstructive pulmonary disorder; and,kidney or renal diseases selected from acute, subacute or chronic formsof glomerulonephritis or membranoproliferative glomerulonephritis,glomerulosclerosis, congenital multicystic renal dysplasia or kidneyfibrosis.

Certain HER1 kinase mediated cancer includes, without limitation,bladder cancer, brain, head or neck cancer, breast cancer, cervicalcancer, colorectal cancer, gastric cancer, glioma cancer, endometrialcancer, esophageal cancer, lung cancer, ovarian cancer, pancreaticcancer or renal cell cancer.

Certain HER2 kinase mediated cancer includes, without limitation,bladder cancer, brain, head or neck cancer, breast cancer, colorectalcancer, gastric cancer, endometrial cancer, esophageal cancer, lungcancer, ovarian cancer, prostate cancer or renal cell cancer.

The term “administering”, with respect to the methods of the presentinvention, refers to a means for treating, ameliorating or preventing adisease, disorder or syndrome as described herein with a compound offormula (I) or a form thereof, which would obviously be included withinthe scope of the invention albeit not specifically disclosed for certainof said compounds.

Such methods include therapeutically or prophylactically administeringan effective amount of compound of formula (I) or a form thereof atdifferent times during the course of a therapy or concurrently in acombination form. Such methods further include administering aneffective amount of said compound with one or more agents at differenttimes during the course of a therapy or concurrently in a combinationform.

The term “prodrug” means a compound of formula (I) or a form thereofthat is converted in vivo into a functional derivative form that maycontribute to therapeutic biological activity, wherein the convertedform may be: 1) a relatively active form; 2) a relatively inactive form;3) a relatively less active form; or, 4) any form which results,directly or indirectly, from such in vivo conversions.

Prodrugs are useful when said compound may be either too toxic toadminister systemically, absorbed poorly by the digestive tract orbroken down by the body before it reaches its target. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described in, for example, “Design of Prodrugs”, ed. H.Bundgaard, Elsevier, 1985.

The term “metabolite” means a prodrug form of a compound of formula (I)or a form thereof converted by in vivo metabolism or a metabolic processto a relatively less active functional derivative of said compound.

The term “subject” as used herein, refers to a patient, such as ananimal, a mammal or a human, who has been the object of treatment,observation or experiment and is at risk of (or susceptible to)developing a disease or disorder or having a disease or disorder relatedto unregulated kinase activity.

The term “effective amount” refers to that amount of a compound offormula (I) or a form, pharmaceutical composition, medicine ormedicament thereof that elicits the biological or medicinal response(such as inhibiting activation of unregulated kinase activity) in atissue system, animal or human, that is being sought by a researcher,veterinarian, medical doctor, or other clinician, which includesalleviation of the symptoms of the disease or disorder being treated.

The effective amount of said compound is from about 0.001 mg/kg/day toabout 300 mg/kg/day.

The term “pharmaceutical composition” refers to a product containing acompound of formula (I) or a form thereof, such as a product comprisingthe specified ingredients in the specified amounts, as well as anyproduct which results, directly or indirectly, from such combinations ofthe specified ingredients in the specified amounts.

The term “medicament” or “medicine” refers to a product containing acompound of formula (I) or a form thereof. The present inventionincludes use of such a medicament for treating, preventing orameliorating a chronic or acute kinase mediated disease, disorder orcondition.

The term “pharmaceutically acceptable” refers to molecular entities andcompositions that are of sufficient purity and quality for use in theformulation of a pharmaceutical composition, medicine or medicament ofthe present invention and that, when appropriately administered to ananimal or a human, do not produce an adverse, allergic or other untowardreaction. Since both human use (clinical and over-the-counter) andveterinary use are equally included within the scope of the presentinvention, a pharmaceutically acceptable formulation would include apharmaceutical composition, medicine or medicament for either human orveterinary use.

The term “combination form” refers to the use of a combination productcomprising a compound of formula (I) or a form, pharmaceuticalcomposition, medicine or medicament thereof and at least one therapeuticagent for treating, preventing or ameliorating a chronic or acuteprotein kinase mediated disease, disorder or condition.

Advantageously, the effective amount of a combination product fortreating, preventing or ameliorating a chronic or acute protein kinasemediated disease, disorder or condition may be a reduced amount ofeither or both the compound or therapeutic agent compared to theeffective amount of the compound or therapeutic agent otherwiserecommended for treating, preventing or ameliorating the disease,disorder or condition. Therefore, it is contemplated that the compoundis administered to the subject before, during or after the time theagent is administered.

The term “therapeutic agent” refers to chemotherapeutic agents used totreat a kinase mediated cancer or antiviral agents used to treatcytomegalovirus. Chemotherapeutic agents include and are not limited toanti-angiogenic agents, anti-tumor agents, cytotoxic agents, inhibitorsof cell proliferation, radiation therapy and the like or a combinationthereof.

The term “treating, preventing or ameliorating” refers, withoutlimitation, to facilitating the eradication of, inhibiting theprogression of or promoting stasis of a chronic or acute kinase mediateddisease, disorder or condition.

The term “radiation therapy” refers to a therapy that comprises exposingthe subject in need thereof to radiation. The present invention includesa method for administering a compound of formula (I) or a form,pharmaceutical composition, medicine or medicament thereof incombination with radiation therapy. Procedures for administering suchtherapy are known to those skilled in the art. The appropriate scheme ofradiation therapy will be similar to those already employed in clinicaltherapies wherein the radiation therapy is used alone or in combinationwith other chemotherapeutic agents.

The present invention includes a pharmaceutical composition comprisingan admixture of a compound of formula (I) or a form thereof and one ormore pharmaceutically acceptable excipients.

The present invention includes a process for making a pharmaceuticalcomposition, medicine or medicament comprising mixing a compound offormula (I) or a form thereof and an optional pharmaceuticallyacceptable carrier. The present invention includes a pharmaceuticalcomposition, medicine or medicament resulting from the process of mixinga compound of formula (I) or a form thereof and an optionalpharmaceutically acceptable carrier. Contemplated processes include bothconventional and unconventional pharmaceutical techniques.

Said pharmaceutical composition, medicine or medicament may take a widevariety of forms to effectuate mode of administration, wherein the modeincludes, and is not limited to, intravenous (both bolus and infusion),oral, nasal, transdermal, topical with or without occlusion, and viainjection intraperitoneally, subcutaneously, intramuscularly,intratumorally, intracerebrally or intracranially. The composition,medicine or medicament may be in a dosage unit such as a tablet, pill,capsule, powder, granule, sterile parenteral solution or suspension,metered aerosol or liquid spray, drop, ampoule, auto-injector device orsuppository for such administration modes.

Pharmaceutical compositions, medicines or medicaments suitable for oraladministration include solid forms such as pills, tablets, caplets,capsules (each including immediate release, timed release and sustainedrelease formulations), granules and powders; and, liquid forms such assolutions, syrups, elixirs, emulsions and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions. Alternatively, the pharmaceutical composition, medicine ormedicament may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection.

The dosage form (tablet, capsule, powder, injection, suppository,teaspoonful and the like) containing the pharmaceutical composition,medicine or medicament contains an effective amount of the activeingredient necessary to be therapeutically or prophylactically effectiveas described above. The pharmaceutical composition, medicine ormedicament may contain from about 0.001 mg to about 5000 mg (preferably,from about 0.001 to about 500 mg) of a compound of formula (I) or a formthereof and may be constituted into any form suitable for the mode ofadministration selected for a subject in need.

An example of a contemplated effective amount for a pharmaceuticalcomposition, medicine or medicament of the present invention may rangefrom about 0.001 mg to about 300 mg/kg of body weight per day. Inanother example, the range is from about 0.003 to about 100 mg/kg ofbody weight per day. In another example, the range is from about 0.005to about 15 mg/kg of body weight per day. The pharmaceuticalcomposition, medicine or medicament may be administered according to adosage regimen of from about 1 to about 5 times per day.

For oral administration, the pharmaceutical composition, medicine ormedicament is preferably in the form of a tablet containing, e.g., 0.01,0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200,250 and 500 milligrams of a compound of formula (I) or a form thereoffor the symptomatic adjustment of the dosage to the patient to betreated.

Optimal dosages will vary depending on factors associated with theparticular patient being treated (e.g., age, weight, diet and time ofadministration), the severity of the condition being treated, theparticular compound being used, the mode of administration and thestrength of the preparation. The use of either daily administration orpost-periodic dosing may be employed.

A representative compound of formula (I) includes a compound selectedfrom:

Cpd Names  1(5E)-4-amino-6-(3-chloro-4-fluoro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  2(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  4(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  6(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-2-oxo-ethyl)-oxime,  7(5E)-4-amino-6-(3-methoxy-4-phenoxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  8(5E)-4-amino-6-(3-methoxy-4-phenoxy-phenylamino)-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-2-oxo-ethyl)-oxime,  9(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  10(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime,  11(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-allyl-oxime,  12(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-tert-butyl-oxime,  13(5E)-4-amino-6-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  16(5E)-4-amino-6-[(1S)-1-phenyl-ethylamino]-pyrimidine-5-carbaldehydeO-ethyl- oxime,  17(5E)-4-amino-6-(1H-indol-5-ylamino)-pyrimidine-5-carbaldehyde O-ethyl-oxime,  18 (5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino)-pyrimidine-5-carbaldehyde O-ethyl-oxime,  19(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime,  24(5E)-4-amino-6-(4-phenoxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  25(5E)-4-amino-6-(4-benzyloxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  29(5E)-4-amino-6-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  30(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-isobutyl-oxime,  31(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-phenoxy-ethyl)-oxime,  32(5E)-4-amino-6-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  33(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime,  34(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  36(5E)-4-amino-6-(3-bromo-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  37(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-ethyl-oxime,  38(5E)-4-amino-6-[3-chloro-4-(pyridin-3-yloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  44(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(4-methoxy-benzyl)-oxime,  45(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-methoxy-benzyl)-oxime,  46(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-benzyl-oxime,  47(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-isopropyl-oxime,  48(5E)-4-amino-6-(1-benzyl-1H-indazol-5-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  49(5E)-4-amino-6-(1-benzyl-1H-indazol-5-ylamino)-pyrimidine-5-carbaldehyde O-ethyl-oxime,  503-{5-[6-amino-(5E)-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-indazol-1-ylmethyl}-benzonitrile,  513-{5-[6-amino-(5E)-5-(ethoxyimino-methyl)-pyrimidin-4-ylamino]-indazol-1-ylmethyl}-benzonitrile,  54(5E)-4-amino-6-[1-(3-chloro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  55(5E)-4-amino-6-[1-(3-chloro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime,  58(5E)-4-amino-6-[2-(3-fluoro-benzyl)-1H-benzoimidazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime,  59(5E)-4-amino-6-(3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  60(5E)-4-amino-6-[2-(3-fluoro-benzyl)-1H-benzoimidazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  65(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-phenyl-oxime,  66(5E)-4-amino-6-[1-(4-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  67(5E)-4-amino-6-[1-(4-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime,  68(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-methoxy-ethyl)-oxime,  69(5Z)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime,  70(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-dimethylamino-propyl)-oxime,  71(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(2-methoxy-ethyl)-oxime,  74(5E)-4-amino-6-[1-(3-fluoro-benzyl)-2,3-dihydro-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  75(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime,  76(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime,  77(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde oxime,  78(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime,  78*(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime monohydrochloride salt, 79 (5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde oxime,  84(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde oxime,  85(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime,  87(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-morpholin-4-yl-propyl)-oxime,  88(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde oxime,  91(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime,  92(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-piperidin-1-yl-propyl)-oxime,  93(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime,  94(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(2-piperidin-1-yl-ethyl)-oxime,  95(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(2-piperidin-1-yl-ethyl)-oxime,  96(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-piperidin-1-yl-ethyl)-oxime,  97(5E)-4-amino-6-[3-chloro-4-(3,5-difluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  98(5E)-4-amino-6-[3-chloro-4-(3,5-difluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde oxime,  99(5E)-4-amino-6-[3-chloro-4-(3,5-difluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime, 100(5E)-4-amino-6-[(1S)-1-phenyl-ethylamino]-pyrimidine-5-carbaldehydeoxime, 101(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime, 102(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-piperidin-1-yl-ethyl)-oxime, 111(5E)-4-amino-6-(4-phenoxy-phenylamino)-pyrimidine-5-carbaldehyde oxime,112 (5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(3-morpholin-4-yl-propyl)-oxime, 114(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-pyridin-2-ylmethyl-oxime, 115(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-[3-(2-methoxy-ethylamino)-propyl]-oxime, 1184-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbonitrile,119 N-benzo[1,3]dioxol-5-ylmethyl-5-[(benzo[1,3]dioxol-5-ylmethylimino)-methyl]-pyrimidine-4,6-diamine, 1204-amino-6-(4-methoxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 121 4-amino-6-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 1224-amino-6-(3,4-dimethoxy-benzylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1234-amino-6-(4-phenoxy-benzylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 124 4-amino-6-(indan-1-ylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1254-amino-6-(1,2,3,4-tetrahydro-naphthalen-1-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1264-amino-6-[1-(4-chloro-phenyl)-ethylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 1274-amino-6-[1-(4-methoxy-phenyl)-ethylamino]-pyrimidine-5-carbaldehydeO-methyl-oxime, 1284-amino-6-(6-phenoxy-pyridin-3-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1294-amino-6-(6-morpholin-4-yl-pyridin-3-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1304-amino-6-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazin-5-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1314-amino-6-(2-fluoro-5-methyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1324-amino-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1334-amino-6-(3-chloro-2-methyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1344-amino-6-(3-methylsulfanyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1354-amino-6-[3-(1-methoxyimino-ethyl)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 1364-amino-6-(3,5-dimethyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 137N-{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-phenyl}-acetamide, 138 4-amino-6-phenylamino-pyrimidine-5-carbaldehydeO-methyl-oxime, 1394-amino-6-(4-morpholin-4-yl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 140 4-amino-6-o-tolylamino-pyrimidine-5-carbaldehydeO-methyl-oxime, 1414-amino-6-(3,4-difluoro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1424-amino-6-(3-fluoro-4-methyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1434-amino-6-(3,4-dichloro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1444-amino-6-(3-chloro-4-methyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1454-amino-6-[5-chloro-2-methyl-4-(2-oxo-2-phenyl-ethyl)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 1464-amino-6-(3-ethyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 147 4-amino-6-(4-isopropyl-phenylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime, 1484-amino-6-(1H-indol-5-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1494-amino-6-(3-trifluoromethyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 150 4-amino-6-m-tolylamino-pyrimidine-5-carbaldehydeO-methyl-oxime, 1514-amino-6-(4-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1524-amino-6-(4-chloro-2-methyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1534-amino-6-(4-phenylamino-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1544-amino-6-(4-diethylamino-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1554-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzoic acidmethyl ester, 1564-amino-6-[4-(methoxyimino-phenyl-methyl)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 1574-(4-acetyl-phenylamino)-6-amino-pyrimidine-5-carbaldehyde O-methyl-oxime, 1584-amino-6-[4-(1-methoxyimino-ethyl)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 159{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-phenyl}-acetonitrile, 1604-amino-6-(2-methoxy-4-phenylamino-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 161N-{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-3-methoxy-phenyl}-acetamide, 1624-amino-6-(4-cyclohexyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1634-amino-6-(naphthalen-1-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1644-amino-6-(4-chloro-naphthalen-1-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1654-amino-6-(2,4-difluoro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1664-amino-6-(2-methylsulfanyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1674-amino-6-(3-fluoro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1684-amino-6-(3,5-dichloro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1694-amino-6-(3,5-dichloro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1704-amino-6-(5-chloro-2-methoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1714-amino-6-(5-chloro-2-methyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1724-amino-6-(4-fluoro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 173 4-amino-6-(biphenyl-4-ylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime, 1744-amino-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1754-amino-6-(3,5-dimethoxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1764-amino-6-(3,4,5-trimethoxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1774-amino-6-(3,4-dimethoxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1784-amino-6-(5,6,7,8-tetrahydro-naphthalen-1-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1794-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-N-pyrimidin-2-yl-benzenesulfonamide, 1803-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzoic acidethyl ester, 181{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzyl}-phosphonic acid diethyl ester, 1824-amino-6-(4-ethyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1834-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-N-(3,5-dimethyl-pyrazin-2-yl)-benzenesulfonamide, 1844-amino-6-(2-methyl-benzothiazol-5-ylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1854-amino-6-[4-(4-methoxy-phenylamino)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 1864-amino-6-(4-dimethylamino-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1874-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-N-(2-diethylamino-ethyl)-benzamide, 1884-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzoic acidbutyl ester, 189 4-amino-6-(indan-4-ylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1904-amino-6-(4′-chloro-biphenyl-4-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1914-amino-6-[6-(4-fluoro-phenoxy)-pyridin-3-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 1924′-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-biphenyl-4-carboxylic acid methyl ester, and 193N-(4-benzyloxy-3-chloro-phenyl)-5-[5-(2-morpholin-4-yl-ethyl)-[1,3,4]oxadiazol-2-yl]-pyrimidine-4,6-diamine.

A representative compound of formula (I) includes a compound selectedfrom:

Cpd Names  1(5E)-4-amino-6-(3-chloro-4-fluoro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  2(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime,  4(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  7(5E)-4-amino-6-(3-methoxy-4-phenoxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,  9(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 10(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime, 11(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-allyl-oxime, 12(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-tert-butyl-oxime, 16(5E)-4-amino-6-[(1S)-1-phenyl-ethylamino]-pyrimidine-5-carbaldehydeO-ethyl- oxime, 17(5E)-4-amino-6-(1H-indol-5-ylamino)-pyrimidine-5-carbaldehyde O-ethyl-oxime, 18 (5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino)-pyrimidine-5-carbaldehyde O-ethyl-oxime, 19(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime, 24(5E)-4-amino-6-(4-phenoxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 25(5E)-4-amino-6-(4-benzyloxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 30(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-isobutyl-oxime, 31(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-phenoxy-ethyl)-oxime, 32(5E)-4-amino-6-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 33(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime, 34(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 36(5E)-4-amino-6-(3-bromo-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 37(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-ethyl-oxime, 44(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(4-methoxy-benzyl)-oxime, 45(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-methoxy-benzyl)-oxime, 46(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-benzyl-oxime, 47(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-isopropyl-oxime, 48(5E)-4-amino-6-(1-benzyl-1H-indazol-5-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 49(5E)-4-amino-6-(1-benzyl-1H-indazol-5-ylamino)-pyrimidine-5-carbaldehyde O-ethyl-oxime, 503-{5-[6-amino-(5E)-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-indazol-1-ylmethyl}-benzonitrile, 513-{5-[6-amino-(5E)-5-(ethoxyimino-methyl)-pyrimidin-4-ylamino]-indazol-1-ylmethyl}-benzonitrile, 54(5E)-4-amino-6-[1-(3-chloro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 55(5E)-4-amino-6-[1-(3-chloro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime, 60(5E)-4-amino-6-[2-(3-fluoro-benzyl)-1H-benzoimidazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 70(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-dimethylamino-propyl)-oxime, 71(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(2-methoxy-ethyl)-oxime, 75(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime, 76(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime, 78(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime,  78*(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime monohydrochloride salt, 79(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde oxime, 84(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde oxime, 85(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime, 87(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-morpholin-4-yl-propyl)-oxime, 88(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde oxime, 91(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime, 92(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-piperidin-1-yl-propyl)-oxime, 93(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime, 94(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(2-piperidin-1-yl-ethyl)-oxime, 101 (5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime, 102 (5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-piperidin-1-yl-ethyl)-oxime, 118 4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbonitrile,120  4-amino-6-(4-methoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime, 124 4-amino-6-(indan-1-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,125  4-amino-6-(1,2,3,4-tetrahydro-naphthalen-1-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 126 4-amino-6-[1-(4-chloro-phenyl)-ethylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, and 128 4-amino-6-(6-phenoxy-pyridin-3-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime.

A representative compound of formula (I) includes a compound selectedfrom:

Cpd Names  2 (5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 10(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime, 11(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-allyl-oxime, 75(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime, 78(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime,  78*(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime monohydrochloride salt,79 (5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde oxime, 88(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde oxime, 91(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime, 93(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime, 94(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(2-piperidin-1-yl-ethyl)-oxime, 101 (5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime, 102 (5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-piperidin-1-yl-ethyl)-oxime, 118 4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5- carbonitrile,125  4-amino-6-(1,2,3,4-tetrahydro-naphthalen-1-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, and 128 4-amino-6-(6-phenoxy-pyridin-3-ylamino)-pyrimidine-5- carbaldehydeO-methyl-oxime.

A representative compound of formula (I) includes a compound selectedfrom:

Cpd Names 1274-amino-6-[1-(4-methoxy-phenyl)-ethylamino]-pyrimidine-5-carbaldehydeO-methyl-oxime, 1304-amino-6-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazin-5-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1314-amino-6-(2-fluoro-5-methyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1324-amino-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1334-amino-6-(3-chloro-2-methyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1344-amino-6-(3-methylsulfanyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1354-amino-6-[3-(1-methoxyimino-ethyl)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 1364-amino-6-(3,5-dimethyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 137N-{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-phenyl}-acetamide, 138 4-amino-6-phenylamino-pyrimidine-5-carbaldehydeO-methyl-oxime, 1394-amino-6-(4-morpholin-4-yl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 140 4-amino-6-o-tolylamino-pyrimidine-5-carbaldehydeO-methyl-oxime, 1414-amino-6-(3,4-difluoro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1424-amino-6-(3-fluoro-4-methyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1434-amino-6-(3,4-dichloro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1444-amino-6-(3-chloro-4-methyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1454-amino-6-[5-chloro-2-methyl-4-(2-oxo-2-phenyl-ethyl)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 1464-amino-6-(3-ethyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1474-amino-6-(4-isopropyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1484-amino-6-(1H-indol-5-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,149 4-amino-6-(3-trifluoromethyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 150 4-amino-6-m-tolylamino-pyrimidine-5-carbaldehydeO-methyl-oxime, 1514-amino-6-(4-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1524-amino-6-(4-chloro-2-methyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1534-amino-6-(4-phenylamino-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1544-amino-6-(4-diethylamino-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1554-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzoic acidmethyl ester, 1564-amino-6-[4-(methoxyimino-phenyl-methyl)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 1574-(4-acetyl-phenylamino)-6-amino-pyrimidine-5-carbaldehydeO-methyl-oxime, 1584-amino-6-[4-(1-methoxyimino-ethyl)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 159{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-phenyl}-acetonitrile,160 4-amino-6-(2-methoxy-4-phenylamino-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 161N-{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-3-methoxy-phenyl}-acetamide, 1624-amino-6-(4-cyclohexyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1634-amino-6-(naphthalen-1-ylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1644-amino-6-(4-chloro-naphthalen-1-ylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1654-amino-6-(2,4-difluoro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1664-amino-6-(2-methylsulfanyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1674-amino-6-(3-fluoro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1684-amino-6-(3,5-dichloro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1694-amino-6-(3,5-dichloro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1704-amino-6-(5-chloro-2-methoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1714-amino-6-(5-chloro-2-methyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1724-amino-6-(4-fluoro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1734-amino-6-(biphenyl-4-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime,174 4-amino-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1754-amino-6-(3,5-dimethoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1764-amino-6-(3,4,5-trimethoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1774-amino-6-(3,4-dimethoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1784-amino-6-(5,6,7,8-tetrahydro-naphthalen-1-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime, 1794-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-N-pyrimidin-2-yl-benzenesulfonamide, 1803-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzoic acidethyl ester, 181{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzyl}-phosphonic acid diethyl ester, 1824-amino-6-(4-ethyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1834-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-N-(3,5-dimethyl-pyrazin-2-yl)-benzenesulfonamide, 1844-amino-6-(2-methyl-benzothiazol-5-ylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1854-amino-6-[4-(4-methoxy-phenylamino)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime, 1864-amino-6-(4-dimethylamino-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1874-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-N-(2-O-diethylamino-ethyl)-benzamide, 1884-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzoic acidbutyl ester, 189 4-amino-6-(indan-4-ylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime, 1904-amino-6-(4′-chloro-biphenyl-4-ylamino)-pyrimidine-5-carbaldehydemethyl-oxime, 1914-amino-6-[6-(4-fluoro-phenoxy)-pyridin-3-ylamino]-pyrimidine-5-O-carbaldehyde O-methyl-oxime, 1924′-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-biphenyl-4-carboxylic acid methyl ester, and 193N-(4-benzyloxy-3-chloro-phenyl)-5-[5-(2-morpholin-4-yl-ethyl)-[1,3,4]oxadiazol-2-yl]-pyrimidine-4,6-diamine.Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic schemes described below and areillustrated more particularly in the specific synthetic examples thatfollow. The general schemes and specific examples are offered by way ofillustration; the invention should not be construed as being limited bythe chemical reactions and conditions expressed.

Except where indicated, starting materials and intermediates used in theschemes and examples are prepared by known methodologies well within theordinary skill of persons versed in the art. No attempt has been made tooptimize the yields obtained in any of the example reactions. Oneskilled in the art would also know how to increase such yields throughroutine variations in materials, solvents, reagents, reaction conditionsand the like.

Compounds of the present invention can also be useful as intermediatesfor conversion to other compounds representative of the presentinvention via functional group transformations.

DSC analysis was were conducted on a TA Instruments Q100. Thecalibration standard was indium. A sample (approximately 2 mg) wasplaced into a TA DSC pan and weight was recorded. Crimped pans were usedfor analysis and the samples were heated under nitrogen (50 cc/min) at arate of 10° C./min, up to a final temperature of 250° C. The data wereprocessed using a thermal analyzer (Universal Analyzer 2000, TAInstruments).

The terms used in describing the invention are commonly used and knownto those skilled in the art. When used herein, the followingabbreviations have the indicated meanings

Abbreviation Meaning AcOH acetic acid Cpd compound DCM dichloromethaneDMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDCI1-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride EtOAcethyl acetate EtOH ethanol h/hr(s)/min(s) hour(s)/min(s) LCMS Rt HighPressure Liquid Chromatography Mass Spectrum Retention Time MeOHmethanol RT/rt/r.t. room temperature TEA or Et₃N triethylamine THFtetrahydrofuran

A solution of Compound A1 (in a suitable solvent such as toluene and thelike) is reacted with a volume of NH₃ gas under suitable conditions toprovide a Compound A2.

A mixture of Compound A2 (in a suitable solvent such as DMSO and thelike) and a reagent (such as triethylamine and the like) is reacted witha Compound A3 to provide a Compound A4.

Alternatively, a mixture of Compound A2 (in a suitable solvent such as2-methoxy-ethanol and the like) is reacted with Compound A3 in thepresence of a catalytic amount of acid (such as aqueous HCl) to provideCompound A4.

A mixture of Compound A4 (in a suitable solvent such as DMSO and thelike) is reacted with NH₂OH hydrochloride to provide a Compound A5,representative of a compound of formula (I).

A mixture of Compound A5 (in a suitable solvent such as DMF and thelike) and a basic reagent (such as cesium carbonate and the like) isreacted with a Compound A6 (wherein Q₁ is a leaving group such as ahalogen atom and the like) to provide a Compound A7, representative of acompound of formula (I).

A solution of Compound A7 (in a suitable solvent such as DMF and thelike) is reacted with a Compound A8 (wherein Q₂ is a leaving group suchas a halogen atom and the like) to provide a Compound A9, representativeof a compound of formula (I).

The Compound A9 is metabolized to provide a Compound A10, representativeof a compound of formula (I).

A mixture of Compound A4 (in a suitable solvent such as DMSO and thelike) is reacted with Compound A11 to provide a Compound A7,representative of a compound of formula (I).

Alternatively, a mixture of Compound A4 (in a suitable solvent such as2-methoxy-ethanol and the like) is reacted with a dihydrochloride saltof Compound A11 in the presence of a base (such as NaOH) to provideCompound A7.

A solution of Compound A1 (in a suitable solvent such as toluene and thelike) is reacted with a Compound A12 in a suitable solvent such as THFunder suitable conditions to provide a Compound A13.

A mixture of Compound A13 (in a suitable solvent such as DMSO and thelike) and a reagent (such as triethylamine and the like) is reacted witha Compound A3 to provide a Compound A14.

A mixture of Compound A14 (in a suitable solvent such as DMSO and thelike) is reacted with Compound All to provide a Compound A9,representative of a compound of formula (I).

A mixture of Compound B1 (in a suitable solvent such as THF and thelike) and a reagent (such as triethylamine and the like) is reacted witha Compound A3 to provide a Compound B2.

A suspension of Compound B2 in N(R₂)H₂ (in a suitable solvent such asMeOH and the like) is reacted to provide a Compound B3, representativeof a compound of formula (I).

A mixture of Compound A14 (in a suitable solvent such as a mixture ofTHF and MeOH and the like) is reacted with a reagent mixture (such as amixture of MnO₂, NaCN, AcOH and the like) to provide a Compound C1.

A suspension of Compound C1 (in a solvent such as 100% EtOH and thelike) was treated with hydrazine to provide a Compound C2.

A mixture of Compound C2 is reacted with a Compound C3 and a reagentmixture (such as EDCI in DMF and the like) to provide a Compound C4.

A solution of Compound C4 (in a solvent such as DCM and the like) isreacted with a reagent mixture (such as Et₃N and toluene sulfonylchloride and the like) to provide a Compound C5, representative of acompound of formula (I).

EXAMPLE 1(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-(2-morpholin-4-yl-ethyl)-oxime (Cpd 78)

NH₃ (g) was blown through a solution of4,6-dichloro-pyrimidine-5-carbaldehyde Compound 1a (50 g, 282.5 mmol) intoluene (565 mL, 0.5M) for 3 mins using a 12C glass frit, then themixture was warmed at 60° C. with stirring for 30 min. NH₃ (g) was blownthrough the reaction mixture a second time for 3 min and the reactionwas heated for 30 mins. NH₃ (g) was blown through the reaction mixture athird time for 3 min and the reaction was heated for a final 20 mins.The reaction mixture was diluted with H₂O (1 L), and extracted withEtOAc (1×750 mL, 3×500 mL). The organic extracts were washed with brine(4×) and dried (Na₂SO₄), then concentrated to afford4-amino-6-chloro-pyrimidine-5-carbaldehyde Compound 1b (38.5 g, 87%) asa yellow solid. ¹H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.74 (br s,1H), 8.58 (br s, 1H), 8.42 (s, 1H).

4-benzyloxy-3-chloro-phenylamine Compound 1c (8.9 g, 38 mmol) was addedto a solution of Compound 1b (6.0 g, 38 mmol) and Et₃N (10.6 mL, 76mmol) in DMSO (38 mL, 1M). The mixture was warmed at 100° C. for 3 hrs.The reaction mixture was cooled, then diluted with H₂O and extractedwith EtOAc (3×). The organic extract was washed with H₂O (4×),concentrated onto SiO₂ (30 g) and purified via column chromatography(Horizon, 65+, 60 to 100% EtOAc/hexanes) to afford4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeCompound 1d (8.29 g, 61%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD,warm) δ 10.15 (s, 1H), 8.05 (s, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.48 (d,J=7.6 Hz, 2H), 7.38 (m, 4H), 7.11 (d, J=8.8 Hz, 1H), 5.18, (s, 2H).

A solution of Compound 1d (3.88 g, 10.9 mmol) and NH₂OH hydrochloride(3.02 g, 43.6 mmol) was warmed in DSMO at 90° C. for 4 hours. Thereaction mixture was cooled, diluted with H₂O and extracted with EtOAc(3×). The combined organic extracts were washed with H₂O (4×), thendried (Na₂SO₄) and concentrated onto SiO₂ (12 g). The residue waspurified via column chromatography (Horizon 65+, 70 to 100%EtOAc/hexanes) to provide4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeoxime Compound 1e (2.65 g (66%) as a yellow solid. ¹H NMR (300 MHz,DMSO-d6) δ 11.26 (s, 1H), 9.82 (s, 1H), 8.64 (s, 1H), 8.03 (s, 1H), 7.81(d, J=2.4 Hz, 1H), 7.45 (m, 6H), 7.23 (m, 3H), 5.20 (s, 2H).

4-(2-chloro-ethyl)-morpholine hydrochloride (1.6 g, 8.9 mmol) was addedto a suspension of Compound 1e (3.3 g, 8.9 mmol) and cesium carbonate(8.6 g, 26.7 g) in DMF (90 mL, 0.1 M). The mixture was warmed at 50° C.for 6 hrs. The reaction mixture was cooled, then diluted with H₂O andextracted with EtOAc (3×). The combined organic extracts were washedwith H₂O (4×), then dried (Na₂SO₄) and concentrated onto SiO₂ (12 g).The residue was purified via column chromatography (Horizon 40+M, 0-6%MeOH/DCM) to provide Compound 78 (3.58 g, 83%) as a yellow solid. ¹H NMR(300 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.72 (s, 1H), 8.03 (s, 1H), 7.83 (d,J=2.7 Hz, 1H), 7.49-7.39 (m, 6H), 7.28 (s, 2H), 7.18 (d, J=9.0 Hz, 1H),5.20 (s, 2H), 4.30 (t, J=5.6 Hz, 2H), 3.58 (m, 4H), 2.66 (t, J=5.6 Hz,2H), 2.47 (m, 4H); MS (ESI) m/z 383 (MH⁺); DSC Thermogram: singleendothermic peak at 175° C. due to melting with onset and peaktemperatures of 174.66° C. and 176.28° C., respectively, and an enthalpyof 142.9 J/g.

Compound 78 was further conjugated with monohydrochloride HCl to provideCompound 78 as a monohydrochloride salt. ¹H NMR (300 MHz, DMSO-d6) δ10.78 (br s, 1H), 9.52 (s, 1H), 8.79 (s, 1H), 8.06 (s, 1H), 7.84 (d,J=2.7 Hz, 1H), 7.51-7.19 (m, 9 H), 7.20 (d, J=9 Hz, 1H), 5.22 (s, 2 H),4.56 (br s, 2 H), 4.03-3.82 (m, 4H), 3.58-3.18 (m, 13H); Anal. Calcd forC₂₄H₂₈Cl₂N₆O₃: C, 55.50; H, 5.43; N, 16.18; Cl, 13.65. Found: C, 55.08;H, 5.41; N, 15.94; Cl, 13.17.

Using the procedure of Example 1, other compounds representative of thepresent invention were prepared:

Cpd Name and Data 1(5E)-4-amino-6-(3-chloro-4-fluoro-phenylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime ¹H NMR (DMSO-d6) δ 9.68 (br, 1H), 8.71 (br, 1H), 8.06(s, 1H), 7.99 (dd, J = 6.78 and 2.80 Hz, 1H), 7.49 (m, 1H), 7.35 (br,2H), 7.34 (m, 1H), 3.96 (s, 3H). LC-MS Rt = 1.08 min, m/z 296.3 (MH⁺) 2(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (DMSO-d6) δ 9.75 (s, 1H), 8.73 (s,1H), 8.09 (t, J = 0.86 Hz, 1H), 8.06 (d, J = 1.86 Hz, 1H), 8.00 (s, 1H),7.64 (d, J = 9.07 Hz, 1H), 7.44 (dd, J = 8.88 and 1.93 Hz, 1H), 7.34 (m,1H), 7.21 (s, 2H), 7.09 (m, 1H), 7.04 (m, 2H), 5.67 (s, 2H), 3.95 (s,3H). LC-MS Rt = 1.19 min, m/z 392.4 (MH⁺) 3(5E)-4-amino-6-(3-chloro-4-fluoro-benzylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime MS m/z 310.1 (MH⁺) 4(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CD₃OD) δ 8.56 (s, 1H), 7.96 (s, 1H),7.68 (d, J = 2.50 Hz, 1H), 7.39 (td, J = 7.98 and 5.58 Hz, 1H), 7.28(dd, J = 8.85 and 2.61 Hz, 2 H), 7.23 (m, 1H), 7.08 (d, J = 8.92 Hz,1H), 7.02 (m, 1H), 5.18 (s, 2H), 3.98 (s, 3H). LC-MS Rt = 1.41 min, m/z402.1 (MH⁺) 5(5E)-4-amino-6-[2-(3-fluoro-benzyl)-2H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CDCl₃) δ 9.60 (s, 1H), 8.34 (d, J =0.50 Hz, 1H), 8.18 (s, 1H), 8.03 (dd, J = 1.83 and 0.45 Hz, 1H), 7.91(br, 1H), 7.71 (dd, J = 9.20 and 0.65 Hz, 1H), 7.31 (m, 1H), 7.23 (m,1H), 7.02 (dd, J = 7.88 and 1.96 Hz, 2H), 6.96 (m, 1H), 5.72 (br, 2H),5.58 (s, 2H), 4.03 (s, 3H). LC-MS Rt = 1.12 min, m/z 392.2 (MH⁺) 6(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-2-oxo-ethyl)-oxime ¹H NMR (CD₃OD) δ8.73 (s, 1H), 8.13 (d, J = 0.92 Hz, 1H), 8.12 (s, 1H), 7.94 (dd, J =1.91 and 0.66 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.44 (dd, J = 8.92 and1.97 Hz, 1H), 7.32 (dt, J = 7.98 and 5.75 Hz, 1H), 7.02 (m, 2H), 6.89(dt, J = 9.66 and 1.79 Hz, 1H), 5.69 (s, 2H), 5.00 (s, 2H), 3.67 (t, J =4.52 Hz, 2H), 3.60 (m, 4H), 3.53 (t, J = 4.85 Hz, 2H). LC-MS Rt = 1.00min, m/z 505.1 (MH⁺) 7(5E)-4-amino-6-(3-methoxy-4-phenoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime ¹H NMR (CDCl₃) δ 9.40 (s, 1H), 8.30 (s, 1H), 8.22 (s,1H), 7.51 (t, J = 1.24 Hz, 1H), 7.29 (m, 2H), 7.03 (tt, J = 7.31 and1.11 Hz, 1H), 6.96 (m, 4H), 5.36 (s, 2H), 4.03 (s, 3H), 3.86 (s, 3H).LC-MS Rt = 1.27 min, m/z 366.1 (MH⁺) 8(5E)-4-amino-6-(3-methoxy-4-phenoxy-phenylamino)-pyrimidine-5-carbaldehydeO-(2-morpholin-4-yl-2-oxo-ethyl)-oxime ¹H NMR (CDCl₃) δ 9.33 (br, 1H),8.46 (s, 1H), 8.22 (s, 1H), 7.49 (d, J = 2.49 Hz, 1H), 7.28 (td, J =7.44 and 1.23 Hz, 2H), 7.13 (dd, J = 8.68 and 2.46 Hz, 1H), 7.03 (tt, J= 7.34 and 1.07 Hz, 1H), 6.95 (m, 3H), 5.50 (br, 2H), 4.84 (s, 2H), 3.88(s, 3H), 3.68 (t, J = 4.80 Hz, 2H), 3.64 (4H), 3.53 (t, J = 4.80 Hz,2H). LC-MS Rt = 1.06 min, m/z 379.2 (MH⁺) 9(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime ¹H NMR (CDCl₃) δ 9.34 (s, 1H), 8.27 (s, 1H), 8.18 (s,1H), 7.66 (d, J = 2.60 Hz, 1H), 7.46 (m, 2H), 7.32-7.42 (4H), 6.94 (d, J= 8.87 Hz, 1 H), 5.33 (br, 2H), 5.16 (s, 2H), 4.01 (s, 3H). LC-MS Rt =1.40 min, m/z 384.1 (MH⁺) 10(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime ¹H NMR (CDCl₃) δ 10.39 (s, 1H), 8.42 (s, 1H),8.10 (m, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.35 (d, J = 1.3 Hz, 1H),7.24-7.33 (4H), 6.83-7.01 (3H), 5.60 (s, 2H), 4.28 (q, J = 7.06 Hz, 2H),1.37 (t, J = 7.04 Hz, 3H). LC-MS Rt = 1.27 min, m/z 406.1 (MH⁺) 11(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-allyl-oxime ¹H NMR (CDCl₃) δ 9.52 (br, 1H), 8.36 (s, 1H),8.17 (s, 1H), 8.04 (d, J = 0.88 Hz, 1H), 7.97 (m, 1H), 7.41 (dd, J =9.05 and 2.1 Hz, 1H), 7.23-7.32 (2H), 6.83-6.98 (3H), 6.06 (m, 1H), 5.58(s, 2H), 5.45 (br, 2H), 5.39 (dq, J = 17.29 and 1.52 Hz, 1H), 5.31 (m,1H), 4.69 (dt, J = 5.98 and 1.35 Hz, 2H). LC-MS Rt = 1.32 min, m/z 418.1(MH⁺) 12(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-tert-butyl-oxime ¹H NMR (CDCl₃) δ 8.30 (s, 1H), 8.18 (s,1H), 8.04 (m, 1H), 8.00 (m, 1H), 7.21-7.36 (4H), 6.84-6.98 (3H), 5.58(s, 2H), 1.41 (s, 9H). LC-MS Rt = 1.45 min, m/z 434.1 (MH⁺) 13(5E)-4-amino-6-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CDCl₃) δ 9.42 (br, 1H), 8.36 (dd, J= 2.81 and 0.60 Hz, 1H), 8.31 (dd, J = 4.41 and 1.60 Hz, 1H), 8.30 (s,1H), 8.20 (s, 1H), 7.48 (d, J = 2.37 Hz, 1H), 7.40 (dd, J = 8.64 and2.74 Hz, 1H), 7.23 (ddd, J = 8.39, 4.37, and 0.80 Hz, 1H), 7.17 (ddd, J= 8.40, 2.75, and 1.65 Hz, 1H), 6.93 (d, J = 8.68 Hz, 1H), 5.45 (br,2H), 4.00 (s, 3H), 2.24 (s, 3H). LC-MS Rt = 0.55 min, m/z 351.1 (MH⁺) 14(5E)-4-amino-6-[(1R)-1-phenyl-ethylamino]-pyrimidine-5-carbaldehydeO-ethyl- oxime ¹H NMR (CDCl₃) δ 8.24 (s, 1H), 8.09 (s, 1H), 7.71 (d, J =6.85 Hz, 1H), 7.31-7.38 (3H), 7.22-7.28 (2H), 5.45 (m, 1H), 5.29 (br,2H), 4.18 (q, J = 7.10 Hz, 2H), 1.57 (d, J = 6.85 Hz, 3H), 1.31 (t, J =7.05 Hz, 3H). LC-MS Rt = 1.19 min, m/z 286.0 (MH⁺) 15(5Z)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde oxime ¹H NMR (CD₃OD) δ 8.54 (s, 1H), 8.05 (d, J = 0.87 Hz,1H), 7.92 (dd, J = 1.90 and 0.72 Hz, 1H), 7.90 (s, 1H), 7.51 (dt, J =8.89 and 0.81 Hz, 1H), 7.41 (dd, J = 8.96 and 1.93 Hz, 1H), 7.30 (td, J= 7.94 and 5.84 Hz, 1H), 7.01 (m, 1H), 6.97 (m, 1H), 6.88 (dt, J = 9.79and 2.27 Hz, 1H), 5.65 (s, 2H). LC-MS Rt = 0.98 min, m/z 378.1 (MH⁺) 16(5E)-4-amino-6-[(1S)-1-phenyl-ethylamino]-pyrimidine-5-carbaldehydeO-ethyl- oxime ¹H NMR (CDCl₃) δ 8.92 (d, J = 7.11 Hz, 1H), 8.42 (s, 1H),8.02 (s, 1H), 7.28-7.39 (5H), 7.23 (br, 2H), 5.47 (m, 1H), 4.17 (q, J =7.02 Hz, 2H), 1.61 (d, J = 6.87 Hz, 3H), 1.28 (t, J = 7.04 Hz, 3H).LC-MS Rt = 1.19 min, m/z 286.1 (MH⁺) 17(5E)-4-amino-6-(1H-indol-5-ylamino)-pyrimidine-5-carbaldehydeO-ethyl-oxime ¹H NMR (CDCl₃) δ 9.42 (br, 1H), 8.33 (s, 1H), 8.15 (s,1H), 7.76 (d, J = 2.03 Hz, 1H), 7.39 (d, J = 8.69 Hz, 1H), 7.24 (m, 2H),6.55 (m, 1H), 5.65 (br, 2H), 4.26 (q, J = 7.05 Hz, 2H), 1.37 (t, J =7.08 Hz, 3H). LC-MS Rt = 0.96 min, m/z 297.0 (MH⁺) 18(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino)-pyrimidine-5-carbaldehyde O-ethyl-oxime ¹H NMR (CDCl₃) δ 9.56 (br, 1H), 8.30 (s, 1H),8.17 (s, 1H), 7.66 (d, J = 2.64 Hz, 1H), 7.34 (m, 2H), 7.21 (m, 2H),7.02 (td, J = 8.20 and 2.37 Hz, 1H), 6.93 (d, J = 8.81 Hz, 1H), 5.62(br, 2H), 5.14 (s, 2H), 4.27 (q, J = 7.05 Hz, 2H), 1.37 (t, J = 7.07 Hz,3H). LC-MS Rt = 1.56 min, m/z 416.1 (MH⁺) 19(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime ¹H NMR (CD₃OD) δ 8.63 (s,1H), 8.05 (d, J = 0.91 Hz, 1H), 7.92 (m, 2H), 7.50 (m, 1H), 7.42 (dd, J= 8.95 and 1.92 Hz, 1H), 7.30 (m, 1H), 7.00 (m, 2H), 6.87 (m, 1H), 5.65(s, 2H), 4.38 (t, J = 5.45 Hz, 2H), 3.71 (t, J = 4.65 Hz, 4H), 2.83 (t,J = 5.46 Hz, 2H), 2.64 (t, J = 4.54 Hz, 4H). LC-MS Rt = 0.84 min, m/z491.2 (MH⁺) 20(5E)-4-amino-6-(indan-5-ylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime ¹H NMR (CDCl₃) δ 9.51 (br, 1H), 8.33 (s, 1H), 8.14 (s,1H), 7.40 (m, 1H), 7.20 (m, 2H), 6.00 (br, 2H), 4.01 (s, 3H), 2.96 (t, J= 7.79 Hz, 2H), 2.90 (t, J = 7.35 Hz, 2H), 2.10 (m, 2H). LC-MS Rt = 1.15min, m/z 284.1 (MH⁺) 21(5E)-4-amino-6-(4-difluoromethoxy-phenylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime ¹H NMR (CDCl₃) δ 10.06 (br, 1H), 8.40 (s, 1H), 8.14 (s,1H), 7.52 (d, J = 8.93 Hz, 2H), 7.16 (d, J = 8.97 Hz, 2H), 6.74 (br,2H), 6.38 (d, J = 73.68 Hz, 1H), 4.04 (s, 3H). Rt = 1.03 min, m/z 310.1(MH⁺) 22 (5E)-4-amino-6-(1H-indazol-5-ylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime ¹H NMR (CDCl₃) δ 8.61 (s, 1H), 8.02 (d, J = 0.96 Hz,1H), 7.94 (s, 1H), 7.92 (dd, J = 1.96 and 0.81 Hz, 1H), 7.53 (dt, J =8.94 and 0.81 Hz, 1H), 7.42 (dd, J = 8.91 and 1.96 Hz, 1H), 4.00 (s,3H). LC-MS Rt = 0.60 min, m/z 284.0 (MH⁺) 23(5E)-4-amino-6-(benzo[1,3]dioxol-5-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CDCl₃) δ 10.20 (br, 1H), 8.33 (s, 1H), 8.10 (s,1H), 7.07 (m, 1H), 6.92 (d, J = 3.14 Hz, 1H), 6.82 (br, 2H), 6.81 (d, J= 1.85 Hz, 1H), 6.03 (s, 2H), 4.04 (s, 3H). LC-MS Rt = 0.65 min(22.93%), m/z 288.1 (MH⁺); Rt = 0.85 min (77.07%), m/z 288.0 (MH⁺) 24(5E)-4-amino-6-(4-phenoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime ¹H NMR (CDCl₃) δ 8.36 (s, 1H), 8.12 (s, 1H), 7.43 (m,2H), 7.36 (m, 3H), 7.14 (m, 1H), 7.04 (m, 3H), 4.05 (s, 3H). LC-MS Rt =1.30 min, m/z 336.1 (MH⁺) 25(5E)-4-amino-6-(4-benzyloxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime ¹H NMR (CDCl₃) δ 9.31 (br, 1H), 8.31 (s, 1H), 8.15 (s,1H), 7.28-7.46 (7H), 6.99 (m, 2H), 5.54 (br, 2H), 5.07 (s, 2H), 4.00 (s,3H). LC-MS Rt = 1.29 min, m/z 350.2 (MH⁺) 26(5E)-4-amino-6-(4-sec-butyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime ¹H NMR (CDCl₃) δ 9.72 (s, 1H), 8.33 (s, 1H), 8.16 (s,1H), 7.43 (d, J = 8.42 Hz, 2H), 7.20 (d, J = 8.44 Hz, 1H), 6.21 (br,2H), 4.02 (s, 3H), 2.59 (m, 1H), 1.58 (dq, J = 7.28 and 7.25 Hz, 2H),1.23 (d, J = 6.94 Hz, 3H), 0.83 (t, J = 7.31 Hz, 3H). LC- MS Rt = 1.35min, m/z 300.2 (MH⁺) 27(5E)-4-amino-6-(4-tert-butyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime ¹H NMR (CDCl₃) δ 8.36 (s, 1H), 8.14 (s, 1H), 7.42 (s,4H), 4.02 (s, 3H), 1.33 (s, 9H). LC-MS Rt = 1.32 min, m/z 300.1 (MH⁺) 28(5E)-4-amino-6-(3-benzyloxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime ¹H NMR (CDCl₃) δ 9.73 (br, 1H), 8.32 (s, 1H), 8.16 (s,1H), 7.24-7.47 (7H), 7.06 (m, 1H), 6.79 (ddd, J = 8.0, 2.33 and 0.65 Hz,1H), 6.12 (br, 2H), 5.09 (s, 2H), 4.02 (s, 3H). LC-MS Rt = 1.32 min, m/z350.1 (MH⁺) 29(5E)-4-amino-6-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CDCl₃) δ 9.41 (s, 1H), 8.31 (s,1H), 8.25 (dd, J = 2.59 and 0.75 Hz, 1H), 8.19 (s, 1H), 7.45 (d, J =2.61 Hz, 1H), 7.35 (dd, J = 8.59 and 2.71 Hz, 1H), 7.12 (dd, J = 8.52and 2.67 Hz, 1H), 7.09 (t, J = 8.43 Hz, 1H), 6.87 (d, J = 8.62 Hz, 1H),5.53 (br, 2H), 4.02 (s, 3H), 2.50 (s, 3H), 2.26 (s, 3H). LC-MS Rt = 0.58min, m/z 365.1 (MH⁺) 30(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-isobutyl-oxime ¹H NMR (CD₃OD) δ 8.62 (s, 1H), 8.05 (d, J= 0.97 Hz, 1H), 7.92 (dd, J = 1.91 and 0.78 Hz, 1H), 7.91 (s, 1H), 7.52(dt, J = 9.01 and 0.83 Hz, 1H), 7.41 (dd, J = 8.98 and 1.95 Hz, 1H),7.30 (m, 1H), 6.99 (m, 2H), 6.87 (m, 1H), 5.66 (s, 2H), 3.97 (d, J =6.72 Hz, 2H), 2.05 (m, 1H), 0.99 (d, J = 6.73 Hz, 6H). LC-MS Rt = 1.67min, m/z 485.1 (MH⁺) 31(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-phenoxy-ethyl)-oxime ¹H NMR (CDCl₃) δ 8.47 (s, 1H),8.10 (m, 1H), 8.05 (s, 1H), 7.85 (m, 1H), 7.21-7.36 (5H), 6.84-7.01(6H), 5.59 (s, 2H), 4.58 (t, J = 4.42 Hz, 2H), 4.28 (t, J = 4.30 Hz,2H). LC-MS Rt = 1.47 min, m/z 498.2 (MH⁺) 32(5E)-4-amino-6-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (DMSO-d6) δ 9.58 (s, 1H), 8.69 (s,1H), 8.58 (m, 1H), 8.02 (s, 1H), 7.87 (td, J = 8.21 and 1.72 Hz, 2H),7.56 (d, J = 7.89 Hz, 1H), 7.37 (m, 2H), 7.27 (br, 2H), 7.17 (d, J =9.08 Hz, 1H), 5.25 (s, 2H), 3.94 (s, 3H). LC-MS Rt = 0.73 min, m/z 385.1(MH⁺) 33(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime ¹H NMR (CDCl₃) δ 9.68 (br, 1H), 8.34 (s, 1H),8.12 (s, 1H), 7.76 (br, 1H), 7.28 (m, 1H), 7.22 (m, 2H), 7.16 (d, J =3.19 Hz, 1H), 6.96 (dt, J = 8.74 and 2.75 Hz, 1H), 6.89 (m, 1H), 6.77(dt, J = 9.55 and 2.27 Hz, 1H), 6.56 (d, J = 3.13 Hz, 1H), 6.11 (br,2H), 5.32 (s, 2H), 4.26 (q, J = 7.09 Hz, 2H), 1.36 (t, J = 7.06 Hz, 3H).LC-MS Rt = 1.44 min, m/z 405.2 (MH⁺) 34(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CD₃OD) δ 8.59 (s, 1H), 7.85 (s, 1H),7.64 (dd, J = 2.02 and 0.57 Hz, 1H), 6.91-6.98 (3H), 7.11 (dd, J = 8.74and 2.01 Hz, 1H), 6.93 (m, 2H), 6.78 (dt, J = 9.95 and 2.18 Hz, 1H),6.51 (dd, J = 3.16 and 0.82 Hz, 1H), 5.41 (s, 2H), 3.96 (s, 3H). LC-MSRt = 1.34 min, m/z 391.1 (MH⁺) 35(5E)-4-amino-6-[2,2-difluoro-2-(6-methyl-pyridin-2-yl)-ethylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CD₃OD) δ 8.41 (s, 1H), 7.85 (s, 1H),7.79 (t, J = 7.81 Hz, 1H), 7.49 (t, J = 7.79 Hz, 1H), 7.35 (d, J = 7.74Hz, 1H), 4.44 (t, J = 13.98 Hz, 2H), 3.81 (s, 3H), 2.56 (s, 3H). LC-MSRt = 0.59 min (32.36%), m/z 323.2 (MH⁺); Rt = 0.88 min (67.64%), m/z323.2 (MH⁺) 36(5E)-4-amino-6-(3-bromo-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CDCl₃) δ 8.31 (br, 1H), 8.17 (s, 1H), 7.78 (m, 1H),7.34-7.44 (3H), 4.07 (s, 3H). LC-MS Rt = 1.07 min, m/z 322.0 (MH⁺). 37(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-ethyl-oxime ¹H NMR (CDCl₃) δ 9.59 (br, 1H), 8.30 (s, 1 H), 8.16 (s, 1H), 7.65 (d, J = 2.64 Hz, 1H), 7.30-7.48 (6H), 6.95 (d, J = 8.87 Hz,1H), 5.73 (br, 2H), 5.16 (s, 2H), 4.27 (q, J = 7.05 Hz, 2 H), 1.37 (t, J= 7.06 Hz, 3H). LC-MS Rt = 1.49 min, m/z 398.1 (MH⁺) 38(5E)-4-amino-6-[3-chloro-4-(pyridin-3-yloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CDCl₃) δ 10.14 (br, 1H), 8.41 (s,1H), 8.38 (m, 2H), 8.19 (s, 1H), 7.81 (d, J = 2.79 Hz, 1H), 7.42 (dd, J= 8.97 and 2.63 Hz, 1H), 7.29 (m, 2H), 7.07 (d, J = 8.84 Hz, 1H), 6.68(br, 2H), 4.06 (s, 3H). LC-MS Rt = 0.55 min, m/z 371.0 (MH⁺) 44(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(4-methoxy-benzyl)-oxime ¹H NMR (CD₃OD) δ 8.60 (s, 1H),8.05 (d, J = 0.96 Hz, 1H), 7.89 (s, 1H), 7.76 (m, 1H), 7.47 (d, J = 8.93Hz, 1H), 7.22-7.36 (4H), 6.94-7.03 (3H), 6.85 (m, 2H), 5.66 (s, 2H),5.11 (s, 2H), 3.68 (s, 3H). LC-MS Rt = 1.41 min, m/z 498.1 (MH⁺) 45(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-methoxy-benzyl)-oxime ¹H NMR (CD₃OD) δ 8.60 (s, 1H),8.05 (d, J = 0.92 Hz, 1H), 7.89 (s, 1H), 7.80 (dd, J = 1.94 and 0.73 Hz,1H), 7.49 (d, J = 8.97 Hz, 1H), 7.37 (dd, J = 7.43 and 2.09 Hz, 1H),7.29 (m, 3H), 6.94-7.03 (3H), 6.88 (m, 2H), 5.66 (s, 2H), 5.22 (s, 2H),3.77 (s, 3H). LC-MS Rt = 1.46 min, m/z 498.0 (MH⁺) 46(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-benzyl-oxime ¹H NMR (CD₃OD) δ 8.64 (s, 1H), 8.04 (d, J =0.88 Hz, 1H), 7.90 (s, 1H), 7.77 (m, 1H), 7.41-7.47 (3H), 7.27-7.36(4H), 7.22 (dd, J = 8.96 and 1.96 Hz, 1H), 6.95-7.02 (2H), 6.87 (dt, J =9.58 and 2.01 Hz, 1H), 5.65 (s, 2H), 5.19 (s, 2H). LC-MS Rt = 1.42 min,m/z 468.1 (MH⁺). 47(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-isopropyl-oxime ¹H NMR (CD₃OD) δ 8.57 (s, 1H), 8.05 (d, J= 0.88 Hz, 1H), 7.94 (dd, J = 1.92 and 0.82 Hz, 1H), 7.92 (s, 1H), 7.51(d, J = 8.92 Hz, 1H), 7.42 (dd, J = 8.99 and 1.95 Hz, 1H), 7.30 (td, J =7.98 and 5.73 Hz, 1H), 6.94-7.02 (2H), 6.87 (dt, J = 9.66 and 2.01 Hz,1H), 5.65 (s, 2H), 4.46 (m, 1H), 1.32 (d, J = 6.24 Hz, 6H). LC-MS Rt =1.34 min, m/z 420.2 (MH⁺) 48(5E)-4-amino-6-(1-benzyl-1H-indazol-5-ylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime ¹H NMR (CD₃OD) δ 8.60 (s, 1H), 8.03 (d, J = 0.91 Hz,1H), 7.92 (d, J = 0.77 Hz, 1H), 7.91 (s, 1H), 7.50 (dt, J = 8.96 and0.74 Hz, 1H), 7.40 (dd, J = 8.93 and 1.91 Hz, 1H), 7.16-7.32 (5H), 5.64(s, 2H), 3.98 (s, 3H). LC-MS Rt = 1.12 min, m/z 374.1 (MH⁺) 49(5E)-4-amino-6-(1-benzyl-1H-indazol-5-ylamino)-pyrimidine-5-carbaldehydeO- ethyl-oxime ¹H NMR (CD₃OD) δ 8.59 (s, 1H), 8.03 (d, J = 0.89 Hz, 1H),7.93 (dd, J = 1.90 and 0.73 Hz, 1H), 7.91 (s, 1H), 7.51 (dt, J = 9.01and 0.78 Hz, 1H), 7.40 (dd, J = 8.94 and 1.94 Hz, 1H), 7.16-7.32 (5H),5.64 (s, 2H), 4.23 (q, J = 7.07 Hz, 2H), 1.34 (t, J = 7.04 Hz, 3H).LC-MS Rt = 1.21 min, m/z 388.1 (MH⁺) 503-{5-[6-amino-(5E)-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-indazol-1-ylmethyl}-benzonitrile ¹H NMR (CD₃OD) δ 8.60 (s, 1H), 8.07 (d, J = 0.91Hz, 1H), 7.93 (dd, J = 1.92 and 0.71 Hz, 1H), 7.92 (s, 1H), 7.63 (td, J= 5.39 and 1.81 Hz, 1H), 7.54 (dt, J = 8.90 and 0.86 Hz, 1H), 7.53 (s,1H), 7.48 (m, 2H), 7.44 (dd, J = 8.95 and 1.94 Hz, 1H), 5.71 (s, 2H),3.98 (s, 3H). LC-MS Rt = 1.08 min, m/z 399.2 (MH⁺) 513-{5-[6-amino-(5E)-5-(ethoxyimino-methyl)-pyrimidin-4-ylamino]-indazol-1-ylmethyl}-benzonitrile ¹H NMR (CD₃OD) δ 8.60 (s, 1H), 8.07 (d, J = 0.91Hz, 1H), 7.94 (dd, J = 1.92 and 0.73 Hz, 1H), 7.92 (s, 1H), 7.62 (td, J= 5.25 and 1.61 Hz, 1H), 7.54 (dt, J = 8.97 and 0.86 Hz, 1H), 7.53 (m,1H), 7.48 (m, 2H), 7.43 (dd, J = 8.95 and 1.96 Hz, 1H), 5.70 (s, 2H),4.24 (q, J = 7.07 Hz, 2H), 1.34 (t, J = 7.08 Hz, 3H). LC-MS Rt = 1.16min, m/z 413.3 (MH⁺) 52(5E)-4-amino-6-(2-benzyl-2H-indazol-5-ylamino)-pyrimidine-5-carbaldehydeO- ethyl-oxime ¹H NMR (CD₃OD) δ 8.59 (s, 1H), 8.22 (d, J = 0.73 Hz, 1H),7.95 (s, 1H), 7.93 (dd, J = 1.98 and 0.76 Hz, 1H), 7.58 (dt, J = 9.21and 0.85 Hz, 1H), 7.27-7.37 (6H), 5.62 (s, 2H), 4.24 (q, J = 7.10 Hz,2H), 1.35 (t, J = 7.05 Hz, 3H). LC-MS Rt = 1.16 min, m/z 388.2 (MH⁺) 54(5E)-4-amino-6-[1-(3-chloro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 9.88 (bs, 1H), 8.44(bs, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.39-7.05 (m, 6H),6.37 (bs, 1H), 5.57 (s, 2H), 4.02 (s, 3H);); LC/MS (m/z) (MH⁺) 408.1(calculated for C₂₀H₁₈ClN₇O, 407.86) 55(5E)-4-amino-6-[1-(3-chloro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 9.63 (bs, 1H), 8.36(s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.96 (m, 1H), 7.43-7.04 (m, 6H),5.68 (bs, 1H), 5.30 (s, 2H), 4.26 (q, J = 7.05 Hz, 2H), 1.37 (t, J =7.05 Hz, 3H); LC/MS (m/z) (MH⁺) 422.1 (calculated for C₂₁H₂₀ClN₇O,421.88) 56(5E)-4-amino-6-[1-(3-methoxy-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 9.89 (bs, 1H), 8.43(s, 1H), 8.12 (s, 1H), 8.04 (s, 1H), 7.91 (bs, 1H), 7.36-7.19 (m, 2H),6.82-6.6.44 (m, 2H), 5.57 (s, 2H), 4.02 (s, 3H), 3.74 (s, 3H); LC/MS(m/z) (MH⁺) 404.2 (calculated for C₂₁H₂₁N₇O₂, 403.44) 57(5E)-4-amino-6-[1-(3-methoxy-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 10.45 (bs, 1H), 8.40(s, 1H), 8.069 (s, 1H), 8.067 (s, 1H), 7.85 (s, 1H), 7.55 (bs, 1H),7.36-7.27 (m, 3H), 6.74 (m, 3H), 5.58 (s, 2H), 4.28 (q, J = 7.08 Hz,2H), 3.75 (s, 3H), 1.37 (t, J = 7.08 Hz, 3H); LC/MS (m/z) (MH⁺) 418.2(calculated for C₂₂H₂₃N₇O₂, 417.46) 58(5E)-4-amino-6-[2-(3-fluoro-benzyl)-1H-benzoimidazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime ¹H NMR (CD₃OD) δ 8.64 (s, 1H), 8.13 (s, 1H),8.11 (d, J = 1.83 Hz, 1H), 7.68 (d, J = 8.77 Hz, 1H), 7.49 (dd, J = 8.82and 1.86 Hz, 1H), 7.43 (m, 1H), 7.07-7.24 (3H), 4.52 (s, 2H), 4.30 (q, J= 7.10 Hz, 2H), 1.36 (t, J = 7.07 Hz, 3H). LC-MS Rt = 0.28 min (68.74%),m/z 406.0 (MH⁺); Rt = 0.76 min (31.26%), m/z 406.2 (MH⁺) 59(5E)-4-amino-6-(3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime ¹H NMR (CDCl₃) δ 9.82 (br, 1H), 8.28 (s, 1H), 8.21 (s,1H), 7.41 (m, 1H), 7.30 (m, 1H), 7.13 (m, 1H), 5.96 (br, 2H), 4.05 (s,3H). LC-MS Rt = 0.56 min (51.88%), m/z 278.0 (MH⁺); Rt = 1.02 min(48.12%), m/z 278.1 (MH⁺) 60(5E)-4-amino-6-[2-(3-fluoro-benzyl)-1H-benzoimidazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CD₃OD) δ 8.59 (s, 1H), 7.94 (s, 1H),7.83 (dd, J = 1.99 and 0.54 Hz, 1H), 7.50 (dd, J = 8.59 and 0.53 Hz,1H), 7.34 (dt, J = 6.09 and 7.96 Hz, 1H), 7.23 (dd, J = 8.60 and 2.01Hz, 1H), 7.14 (dt, J = 7.60 and 0.75 Hz, 1H), 7.06 (dt, J = 9.98 and1.94 Hz, 1H), 6.99 (td, J = 8.84 and 2.87 Hz, 1H), 4.27 (s, 2H), 3.99(s, 3H). LC-MS Rt = 0.55 min, m/z 392.1 (MH⁺) 61(5E)-4-amino-6-[4-(3-fluoro-benzyloxy)-3-methoxy-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 9.32 (bs, 1H), 8.32(s, 1H), 8.16 (s, 1H), 7.36-7.02 (m, 4H), 6.91-6.82 (m, 3H), 5.62 (bs,1H), 5.13 (s, 2H), 3.998 (s, 3H), 3.91 (s, 3H); LC/MS (m/z) (MH⁺) 398.1(calculated for C₂₀H₂₀FN₅O₃, 397.40) 62(5E)-4-amino-6-[4-(3-fluoro-benzyloxy)-3-methoxy-phenylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 9.51 (bs, 1H), 8.32(s, 1H), 8.15 (s, 1H), 7.36-7.16 (m. 4H), 7.02-6.82 (m, 3H), 5.80 (bs,1H), 5.13 (s, 2H), 4.25 (q, J = 7.06 Hz, 2H), 3.91 (s, 3H), 1.36 (t, J =7.06 Hz, 3H);); LC/MS (m/z) (MH⁺) 412.2 (calculated for C₂₁H₂₂FN₅O₃,411.43) 63(5E)-4-amino-6-(3-chloro-4-methoxy-phenylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime ¹H NMR (CDCl₃) δ 9.32 (br, 1H), 8.28 (s, 1H), 8.18 (s,1H), 7.61 (d, J = 2.63 Hz, 1H), 7.39 (dd, J = 8.85 and 2.63 Hz, 1H),6.93 (d, J = 8.86 Hz, 1H), 5.39 (br, 2H), 4.02 (s, 3H), 3.90 (s, 3H).LC-MS Rt = 1.00 min, m/z 308.1 (MH⁺) 64(5E)-4-amino-6-(3-chloro-4-morpholin-4-yl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CDCl₃) δ 9.43 (br, 1H), 8.28 (s,1H), 8.19 (s, 1H), 7.66 (d, J = 2.51 Hz, 1H), 7.41 (dd, J = 8.71 and2.66 Hz, 1H), 7.04 (d, J = 8.68 Hz, 1H), 5.45 (br, 2H), 4.02 (s, 3H),3.88 (t, J = 4.59 Hz, 4H), 3.04 (t, J = 4.55 Hz, 4H). LC-MS Rt = 1.02min, m/z 363.1 (MH⁺) 65(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-phenyl-oxime ¹H NMR (CDCl₃) δ 8.70 (s, 1H), 8.21 (s, 1H),8.04 (s, 1H), 7.99 (s, 1H), 6.81-7.44 (10H), 5.58 (s, 2H). LC-MS Rt =1.44 min, m/z 454.2 (MH⁺) 66(5E)-4-amino-6-[1-(4-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 9.64 (bs, 1H), 8.38(s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.42-7.16 (m, 4H),7.01-6.95 (m, 2H), 5.92 (bs, 2H), 5.56 (s, 2H), 4.01 (s, 3H); LC/MS(m/z) (MH⁺) 392.2 (calculated for C₂₀H₁₈FN₇O, 391.40) 67(5E)-4-amino-6-[1-(4-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 9.73 (bs, 1H), 8.37(s, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.41-7.16 (m, 4H),7.01-6.95 (m, 2H), 5.94 (bs, 1H), 5.56 (s, 2H), 4.25 (q, J = 7.06 Hz,2H), 1.36 (t, J = 7.06 Hz, 3H); LC/MS (m/z) (MH⁺) 406.2 (calculated forC₂₁H₂₀FN₇O, 405.43) 68(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-methoxy-ethyl)-oxime ¹H NMR (CD₃OD) δ 8.60 (s. 1H),8.05 (d, J = 0.89 Hz, 1H), 7.93 (dd, J = 1.91 and 0.75 Hz, 1H), 7.92 (s,1H), 7.51 (dt, J = 8.97 and 0.76 Hz, 1H), 7.43 (dd, J = 8.94 and 1.93Hz, 1H), 7.30 (td, J = 7.97 and 5.95 Hz, 1H), 7.01 (m, 1H), 6.96 (m,1H), 6.87 (dt, J = 9.70 and 1.71 Hz, 1H), 5.65 (s, 1H), 4.32 (t, J =4.49 Hz, 2H), 3.71 (t, J = 4.60 Hz, 2H), 3.35 (s, 3H). LC-MS Rt = 1.13min, m/z 436.2 (MH⁺) 69(5Z)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime ¹H NMR (CD₃OD) δ 8.62 (s, 1H),8.05 (d, J = 0.89 Hz, 1H), 7.93 (dd, J = 1.91 and 0.75 Hz, 1H), 7.91 (s,1H), 7.46 (m, 2H), 7.30 (m, 1H), 7.01 (m, 1H), 6.87-6.96 (2H), 5.65 (s,2H), 4.28 (t, J = 6.48 Hz, 2H), 3.69 (t, J = 6.35 Hz, 2H), 1.94 (m, 2H).LC-MS Rt = 0.55 min, m/z 436.3 (MH⁺) 70(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-dimethylamino-propyl)-oxime ¹H NMR (CDCl₃) δ 9.38 (br,1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 0.73 Hz, 1H), 7.97 (d, J =1.92 Hz, 1H), 7.42 (dd, J = 8.87 and 1.91 Hz, 1H), 7.23-7.37 (2H),6.91-6.98 (2H), 6.86 (m, 1H), 5.58 (s, 2H), 5.21 (br, 2H), 4.26 (t, J =6.51 Hz, 2H), 2.41 (t, J = 7.05 Hz, 2H), 2.24 (s, 6H), 1.92 (m, 2H).LC-MS Rt = 0.29 min (37.41%), m/z 463.2 (MH⁺); Rt = 0.76 min (62.59%),m/z 463.2 (MH⁺) 71(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-(2-methoxy-ethyl)-oxime ¹H NMR (CD₃OD) δ 8.56 (s, 1H), 7.95 (s, 1H),7.66 (d, J = 2.58 Hz, 1H), 7.47 (m, 2H), 7.28-7.40 (4H), 7.08 (d, J =8.89 Hz, 1H), 5.16 (s, 2H), 4.32 (t, J = 4.45 Hz, 2H), 3.71 (t, J = 4.58Hz, 2H), 3.36 (s, 3H). LC-MS Rt = 1.36 min, m/z 428.1 (MH⁺) 72(5E)-4-amino-6-[2-(3-fluoro-phenyl)-benzofuran-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 9.80 (bs, 1H), 8.44(s, 1H), 8.15 (s, 1H), 7.82 (d, J = 2.16 Hz, 1H), 7.64-7.26 (m, 5H),7.09-7.03 (m, 2H), 6.24 (bs, 1H), 4.03 (s, 3H); LC/MS (m/z) (MH⁺) 378.2(calculated for C₂₀H₁₆FN₅O₂, 377.37) 73(5E)-4-amino-6-(2-benzyl-benzofuran-5-ylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 9.35 (bs, 1H), 8.33 (s, 1H),8.14 (s, 1H), 7.69 (d, J = 2.12 Hz, 1H), 7.38-7.21 (m, 8H), 5.55 (bs,1H), 4.10 (s, 2H), 3.99 (s, 3H); LC/MS (m/z) (MH⁺) 374.1 (calculated forC₂₁H₁₉N₅O₂, 373.41) 74(5E)-4-amino-6-[1-(3-fluoro-benzyl)-2,3-dihydro-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (CDCl₃) δ 9.07 (s, 1H), 8.29 (s,1H), 8.13 (s, 1H), 7.29 (td, J = 7.55 and 5.49 Hz, 1H), 7.24 (m, 1H),7.14 (d, J = 8.01 Hz, 1H), 7.09 (dd, J = 9.89 and 2.23 Hz, 1H), 7.04(dd, J = 8.71 and 2.05 Hz, 1H), 6.96 (td, J = 8.11 and 2.65 Hz, 1H),6.42 (d, J = 8.31 Hz, 1H), 5.42 (br, 2H), 4.23 (s, 2H), 3.98 (s, 3H),3.36 (t, J = 8.19 Hz, 2H), 3.01 (t, J = 8.29 Hz, 2H); LC-MS Rt = 1.48min, m/z 393.3 (MH⁺) 75(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime ¹H NMR (300 Hz, CDCl₃) δ 8.56(s, 1H), 7.96 (s, 1H), 7.70 (d, J = 2.55 Hz, 1H), 7.01-7.00 (m, 6H),5.17 (s, 2H), 4.29 (t, J = 6.35 Hz, 2H), 3.70 (d, J = 6.35 Hz, 2H), 1.96(m, 2H); LC/MS (m/z) 446.2 (MH⁺) (calculated for C₂₁H₂₁ClFN₅O₃, 445.87).76(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-(3-hydroxy-propyl)-oxime ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.97(s, 1H), 7.67 (d, j = 2.5, 1H), 7.46 (d, j = 7.1, 2H), 7.38-7.25 (m,4H), 7.06 (d, j = 8.9, 1H), 5.15 (s, 2H), 4.28 (t, j = 12.5, 2H), 3.70(t, j = 12.7, 2H), 1.97-1.94 (m, 2H); MS (ESI) m/z 427, 428 (MH⁺), 426(MH−) 77(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeoxime ¹H NMR (300 MHz, CD₃OD) δ 8.52 (s, 1H), 7.96 (s, 1H), 7.66 (d, J =2.4 Hz, 1H), 7.50-7.29 (m, 6H), 7.10 (d, J = 9 Hz, 1H), 5.17 (s, 2H); MS(ESI) m/z 370 (MH⁺) 79(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde oxime ¹H NMR (300 MHz, CD₃OD) δ 8.51 (s, 1H), 7.95 (s, 1H),7.66 (d, J = 2.4 Hz, 1H), 7.40-7.04 (m, 7H), 5.17 (s, 2H) 80(5E)-4-amino-6-(4-chloro-2-fluoro-phenylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime MS m/z 296.1 (MH⁺) 81(5Z)-4-amino-6-(4-chloro-2-fluoro-phenylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime MS m/z 296.1 (MH⁺) 82(5E)-4-amino-6-(4-bromo-2-fluoro-phenylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime MS m/z 340 (MH⁺) 83(5Z)-4-amino-6-(4-bromo-2-fluoro-phenylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime MS m/z 340 (MH⁺) 84(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde oxime ¹H NMR (300 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.92 (s,1H), 8.65 (s, 1H), 8.09 (s, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.97 (s, 1H),7.65 (d, J = 9.0 Hz, 1H), 7.44-7.36 (m, 2H), 7.11-7.03 (m, 5H), 5.66 (s,2H); MS (ESI) m/z 376 (MH⁺) 85(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime ¹H NMR (300 MHz, CDCl₃) δ 9.40(s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H),7.40-7.25 (m, 2H), 6.98-6.84 (m, 3H), 5.58 (s, 2H), 5.33 (br s, 2H),4.37 (t, J = 5.7 Hz, 2H), 3.83 (t, J = 12.3 Hz, 2H), 2.04 (m, 2H); MS(ESI) m/z 434 (MH⁺) 86(5E)-4-(4-bromo-2-fluoro-phenylamino)-6-methoxyamino-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 370 (MH⁺) 87(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-morpholin-4-yl-propyl)-oxime ¹H NMR (300 MHz, CDCl₃) δ9.37 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H),7.42 (dd, J = 9.0, 1.8 Hz, 1H), 7.30-7.24 (m, #H), 6.97-6.83 (m, 3H),5.57 (s, 2H), 5.34 (s, 2H), 4.26 (t, J = 6.3 Hz, 2H), 3.72 (m, 4H), 2.52(m, 6H), 1.95 (m, 2H); MS (ESI) m/z 505 (MH⁺) 88(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde oxime ¹H NMR (300 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.89 (s,1H), 8.65 (s, 1H), 7.95 (s, 1H), 7.81 (d, J = 1.5 Hz, 1H), 7.52 (d, J =3.0 Hz, 1H), 7.42-7.02 (m, 7H), 6.48 (d, J = 2.7 Hz, 1H), 5.44 (s, 2H);MS (ESI) m/z 377 (MH⁺) 89(5E)-4-amino-6-(4-chloro-2-fluoro-5-hydroxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 312.1 (MH⁺) 90(5Z)-4-amino-6-(4-chloro-2-fluoro-5-hydroxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 312.1 (MH⁺) 91(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-hydroxy-propyl)-oxime ¹H NMR (300 MHz, DMSO-d6) δ 9.74(s, 1H), 8.74 (s, 1H), 7.98 (s, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.53 (d,J = 3.3 Hz, 1H), 7.38-7.34 (m, 2H), 7.20-7.00 (m, 6H), 6.49 (d, J = 3.0Hz, 1H), 5.78 (s, 2H), 4.56 (t, J = 5.1 Hz, 1H), 4.24 (t, J = 6.3 Hz,2H), 3.55 (m, 2H), 1.86 (m, 2H); MS (ESI) m/z 435 (MH⁺) 92(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(3-piperidin-1-yl-propyl)-oxime ¹H NMR (300 MHz, CD₃OD) δ8.62 (s, 1H), 8.05 (s, 1H), 7.92 (s, 1H), 7.52 (m, 2H), 7.40 (m, 1H),7.02-6.85 (m, 3H), 5.65 (s, 2H), 4.23 (t, J = 6.3 Hz, 2H), 2.60 (m, 6H),2.00 (m, 2H), 1.61 (m, 4H), 1.47 (m, 2H); MS (ESI) m/z 503 (MH⁺) 93(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime ¹H NMR (300 MHz, CD₃OD) δ8.59 (s, 1H), 7.98 (s, 1H), 7.68 (d, J = 2.7 Hz, 1H), 7.42-7.26 (m, 4H),7.10-7.06 (m, 2H), 5.20 (s, 2H), 4.38 (t, J = 5.7 Hz, 2H), 3.71 (t, J =4.8 Hz, 4H), 2.78 (t, J = 5.7 Hz, 2H), 2.59 (t, J = 4.5 Hz, 4H); MS(ESI) m/z 499 (MH⁺) 94(5E)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(2-piperidin-1-yl-ethyl)-oxime ¹H NMR (300 MHz, DMSO-d6)δ 9.63 (s, 1H), 8.72 (s, 2H), 8.03 (s, 1H), 7.85 (d, J = 3.0 Hz, 1H),7.49-7.17 (m, 7H), 5.23 (s, 3H), 4.27 (t, J = 6.0 Hz, 2H), 2.61 (t, J =5.4 Hz, 2H), 2.50 (m, 4H), 1.51-1.37 (m, 6H); MS (ESI) m/z 499 (MH⁺) 95(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-(2-piperidin-1-yl-ethyl)-oxime ¹H NMR (300 MHz, DMSO-d6) δ 9.63 (s,1H), 8.72 (s, 1H), 8.03 (s, 1H), 7.85 (d, J = 3.0 Hz, 1H), 7.50-7.18 (m,9H), 5.21 (s, 2H), 4.28 (t, J = 6.0 Hz, 2H), 2.61 (t, J = 6.0 Hz, 2H),2.39 (m, 4H), 1.49 (m, 4H), 1.39 (m, 2H); MS (ESI) m/z 481 (MH⁺) 96(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-piperidin-1-yl-ethyl)-oxime ¹H NMR (400 MHz, DMSO-d6)δ 9.78 (s, 1H), 8.74 (s, 1H), 8.08 (d, j = 302, 2H), 7.99 (s, 1H), 7.64(d, j = 9.0, 1H), 7.44-7.32 (m, 2H), 7.19 (s, 2H), 7.11-7.01 (m, 3H),5.67 (s, 2H), 4.27 (t, j = 11.6, 2H), 2.61 (t, j = 11.5, 2H), 2.49-2.39(m, 4H), 1.50-1.45 (m, 4H), 1.35 (d, j = 5.0, 2H) 97(5E)-4-amino-6-[3-chloro-4-(3,5-difluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H),8.71 (s, 1H), 8.04 (s, 1H), 7.88 (d, J = 2.7 Hz, 1H), 7.42 (dd, J = 9.3,2.7 Hz, 1H), 7.30-7.16 (m, 6H), 5.25 (s, 2H), 3.98 (s, 3H); MS (ESI) m/z420 (MH⁺) 98(5E)-4-amino-6-[3-chloro-4-(3,5-difluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde oxime ¹H NMR (300 MHz, DMSO-d6) δ 11.25 (s, 1H), 9.81 (s,1H), 8.62 (s, 1H), 8.01 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.42 (dd, J =9.0, 2.7 Hz, 1H), 7.23-7.17 (m, 6H), 5.23 (s, 2H); MS (ESI) m/z 406(MH⁺) 99(5E)-4-amino-6-[3-chloro-4-(3,5-difluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime ¹H NMR (300 MHz, DMSO-d6)δ 9.61 (s, 1H), 8.73 (s, 1H), 8.04 (s, 1H), 7.87 (d, J = 2.7 Hz, 1H),7.42 (dd, J = 8.7, 2.7 Hz, 1H), 7.29-7.16 (m, 6H), 5.24 (s, 2H), 4.30(t, J = 5.7 Hz, 2H), 3.58 (m, 4H), 2.66 (t, J = 5.7 Hz, 2H), 2.45 (m,4H); MS (ESI) m/z 519 (MH⁺) 100(5E)-4-amino-6-[(1S)-1-phenyl-ethylamino]-pyrimidine-5-carbaldehydeoxime MS m/z 258.1 (MH⁺) 101(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime ¹H NMR (400 MHz, DMSO-d6)δ 9.72 (s, 1H), 8.73 (s, 1H), 7.95 (s, 1H), 7.83 (d, j = 1.7, 1H), 7.50(d, j = 3.0, 1H), 7.38-7.32 (m, 2H), 7.18-6.97 (m, 6H), 6.46 (d, j =2.9, 1H), 5.43 (s, 2H), 4.27 t, j = 11.3, 2H), 3.55 (t, j = 9.0, 4H),2.65 (t, j = 11.3, 2H), 2.50-2.44 (m, 4H); MS (ESI) m/z 490 (MH⁺), 488(MH−) 102(5E)-4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbaldehyde O-(2-piperidin-1-yl-ethyl)-oxime ¹H NMR (400 MHz, CD₃OD) δ8.61-8.59 (m, 1H), 7.86-7.83 (m, 1H), 7.64-7.62 (m, 1H), 7.32-7.25 (m,3H), 7.12-7.08 (m, 1H), 6.96-6.94 (m, 2H), 6.77 (d, j = 9.3, 1H),6.51-6.48 (m, 1H), 5.41-5.38 (m, 2H), 4.35-4.31 m, 2H), 2.77-2.74 (m,2H), 2.53 (s, 1H), 1.59 (s, 4H), 1.45 (s, 2H); MS (ESI) m/z 488 (MH⁺),486 (MH−) 103(5E)-4-amino-6-[(1S)-1-phenyl-ethylamino]-pyrimidine-5-carbaldehydeO-(2- morpholin-4-yl-ethyl)-oxime MS m/z 371.2 (MH⁺) 104N-{4-[6-amino-(5E)-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-phenyl}-benzamide MS m/z 363.2 (MH⁺) 105N-{4-[6-amino-(5E)-5-(hydroxyimino-methyl)-pyrimidin-4-ylamino]-phenyl}-benzamide MS m/z 349.1 (MH⁺) 106(5E)-4-amino-6-[(1S)-1-phenyl-ethylamino]-pyrimidine-5-carbaldehydeO-(2- piperidin-1-yl-ethyl)-oxime MS m/z 369.2 (MH⁺) 107N-(4-{6-amino-(5E)-5-[(2-morpholin-4-yl-ethoxyimino)-methyl]-pyrimidin-4-ylamino}-phenyl)-benzamide MS m/z 462.2 (MH⁺) 108(5E)-4-amino-6-(3-chloro-4-fluoro-phenylamino)-pyrimidine-5-carbaldehydeO-(2- morpholin-4-yl-ethyl)-oxime ¹H NMR (400 MHz, CD₃OD) δ 8.58 (d, j =2.6, 1H), 8.00 (d, j = 2.2, 1H), 7.82-7.80 (m, 1H), 7.40-7.36 (m, 1H),7.20-7.16 (m, 1H), 4.37 (t, j = 12.1, 2H), 3.71-3.69 (m, 4H), 2.77 (t, j= 11.1, 2H), 2.58 (d, j = 4.8, 4H); MS (ESI) m/z 394, 395 (MH⁺) 396 109(5E)-4-amino-6-(4-phenoxy-phenylamino)-pyrimidine-5-carbaldehyde O-(2-morpholin-4-yl-ethyl)-oxime ¹H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H),7.42-7.34 (m, 4H), 7.13-7.05 (m, 6H), 4.02 (t, j = 13.3, 2H), 3.50 (d, j= 4.0, 4H), 2.52-2.50 (m, 2H), 2.33 (s, 4H) 110N-{5-[6-amino-(5E)-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-pyrimidin-2-yl}-benzamide MS m/z 365.1 (MH⁺) 111(5E)-4-amino-6-(4-phenoxy-phenylamino)-pyrimidine-5-carbaldehyde oximeMS m/z 322.1 (MH⁺) 112(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-(3-morpholin-4-yl-propyl)-oxime ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s,1H), 7.95 (s, 1H), 7.66 (d, j = 2.5, 1H), 7.46 (d, j = 7.1, 2H),7.38-7.26 (m, 4H), 7.06 (d, j = 28.9, 1H), 5.15 (s, 1H), 4.23 (t, j =12.5, 2H), 3.67 (t, j = 9.6, 4H), 2.53-2.46 (m, 6H), 2.00-1.90 (m, 2H);MS (ESI) m/z 497 (MH⁺) 113 methanesulfonic acid(5E)-3-[4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidin-5-ylmethyleneaminooxy]-propyl ester ¹H NMR (400 MHz, CD₃OD) δ8.58 (s, 1H), 7.95 (s, 1H), 7.67 (d, j = 2.4, 1H), 7.47-7.45 (m, 2H),7.38-7.23 (m, 4H), 7.07-7.04 (m, 1H), 5.14 (s, 2H), 4.38 (t, j = 12.4,2H), 4.30 (t, j = 12.2, 2H), 3.07 (s, 3H), 2.18-2.15 (m, 2H) 114(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-pyridin-2-ylmethyl-oxime ¹H NMR (400 MHz, CD₃OD) δ 8.66 (s, 1H),8.52-8.49 (m, 1H), 7.92 (s, 1H), 7.85-7.80 (m, 1H), 7.58-7.55 (m, 1H),7.49-7.42 (m, 3H), 7.40-7.28 (m, 4H), 7.16-7.12 (m, 1H), 7.05-7.01 (m,1H), 5.28 (s, 2H), 5.16 (s, 2H) 115(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-[3-(2-methoxy-ethylamino)-propyl]-oxime ¹H NMR (400 MHz, CD₃OD) δ 8.56(s, 1H), 7.95 (s, 1H), 7.66 (d, j = 2.4, 1H), 7.46 (d, j = 7.6, 2H),7.38-7.24 (m, 4H), 7.05 (d, j = 8.9, 1H), 5.14 (s, 2H), 4.25 (t, j =12.3, 2H), 3.49-3.47 (m, 2H), 3.31-3.29 (m, 3H), 2.80-2.76 (m, 4H),1.99-1.92 (m, 2H); MS (ESI) m/z 512, 485 (MH⁺), 483 (MH−) 116(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-[3-(4-hydroxy-piperidin-1-yl)-propyl]-oxime ¹H NMR (400 MHz, CD₃OD) δ8.55 (s, 1H), 7.95 (s, 1H), 7.66 (d, j = 2.4, 1H), 7.47-7.25 (m, 6H),7.05 (d, j = 8.9, 1H), 5.14 (s, 2H), 4.21 (t, j = 12.0, 2H), 3.62 (s,1H), 2.84-2.81 (m, 2H), 2.54-2.50 (m, 2H), 2.22-2.18 (m, 2H), 1.98-1.91(m, 2H), 1.87-1.83 (m, 2H), 1.60-1.51 (m, 2H); MS (ESI) m/z 511, 512(MH⁺), 513, 509, 510 (MH−) 117(5E)-4-[4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidin-5-ylmethyleneaminooxymethyl]-piperidine-1-carboxylic acid tert-butyl ester¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.95 (s, 1H), 7.65 (d, j = 2.6,1H), 7.48-7.45 (m, 2H), 7.39-7.35 (m, 2H), 7.34-7.23 (m, 2H), 7.09-7.05(m, 1H), 5.15 (s, 2H), 4.06 (d, j = 6.4, 4H), 2.82-2.75 (m, 2H),1.81-1.74 (m, 2H), 1.44 (s, 9H), 1.30-1.17 (m, 2H); MS (ESI) m/z 567(MH⁺), 565 (MH−) 119N-benzo[1,3]dioxol-5-ylmethyl-5-[(benzo[1,3]dioxol-5-ylmethylimino)-methyl]-pyrimidine-4,6-diamine MS m/z 406 (MH⁺) 1204-amino-6-(4-methoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 274 (MH⁺) 1214-amino-6-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-pyrimidine-5-carbaldehydeO- methyl-oxime MS m/z 302 (MH⁺) 1224-amino-6-(3,4-dimethoxy-benzylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 318 (MH⁺) 1234-amino-6-(4-phenoxy-benzylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 350 (MH⁺) 1244-amino-6-(indan-1-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MSm/z 284 (MH⁺) 1254-amino-6-(1,2,3,4-tetrahydro-naphthalen-1-ylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 298 (MH⁺) 1264-amino-6-[1-(4-chloro-phenyl)-ethylamino]-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 306 (MH⁺) 1274-amino-6-[1-(4-methoxy-phenyl)-ethylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 302 (MH⁺) 1284-amino-6-(6-phenoxy-pyridin-3-ylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 337 (MH⁺) 1294-amino-6-(6-morpholin-4-yl-pyridin-3-ylamino)-pyrimidine-5-carbaldehydeO- methyl-oxime MS m/z 330 (MH⁺) 1304-amino-6-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazin-5-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 328 (MH⁺) 1314-amino-6-(2-fluoro-5-methyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 276 (MH⁺) 1324-amino-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 286 (MH⁺) 1334-amino-6-(3-chloro-2-methyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 292 (MH⁺) 1344-amino-6-(3-methylsulfanyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 290 (MH⁺) 1354-amino-6-[3-(1-methoxyimino-ethyl)-phenylamino]-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 315 (MH⁺) 1364-amino-6-(3,5-dimethyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 272 (MH⁺) 137N-{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-phenyl}-acetamide MS m/z 301 (MH⁺) 1384-amino-6-phenylamino-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z244 (MH⁺) 1394-amino-6-(4-morpholin-4-yl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 329 (MH⁺) 1404-amino-6-o-tolylamino-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z258 (MH⁺) 1414-amino-6-(3,4-difluoro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 280 (MH⁺) 1424-amino-6-(3-fluoro-4-methyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 276 (MH⁺) 1434-amino-6-(3,4-dichloro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 312 (MH⁺) 1444-amino-6-(3-chloro-4-methyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 292 (MH⁺) 1454-amino-6-[5-chloro-2-methyl-4-(2-oxo-2-phenyl-ethyl)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 410 (MH⁺) 1464-amino-6-(3-ethyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oximeMS m/z 272 (MH⁺) 1474-amino-6-(4-isopropyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 286 (MH⁺) 1484-amino-6-(1H-indol-5-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oximeMS m/z 283 (MH⁺) 1494-amino-6-(3-trifluoromethyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 312 (MH⁺) 1504-amino-6-m-tolylamino-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z258 (MH⁺) 151 4-amino-6-(4-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 278 (MH⁺) 1524-amino-6-(4-chloro-2-methyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 292 (MH⁺) 1534-amino-6-(4-phenylamino-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 335 (MH⁺) 1544-amino-6-(4-diethylamino-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 315 (MH⁺) 1554-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzoic acidmethyl ester MS m/z 302 (MH⁺) 1564-amino-6-[4-(methoxyimino-phenyl-methyl)-phenylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 377 (MH⁺) 1574-(4-acetyl-phenylamino)-6-amino-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 286 (MH⁺) 1584-amino-6-[4-(1-methoxyimino-ethyl)-phenylamino]-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 315 (MH⁺) 159{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-phenyl}-acetonitrileMS m/z 283 (MH⁺) 1604-amino-6-(2-methoxy-4-phenylamino-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 365 (MH⁺) 161N-{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-3-methoxy-phenyl}-acetamide MS m/z 331 (MH⁺) 1624-amino-6-(4-cyclohexyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 326 (MH⁺) 1634-amino-6-(naphthalen-1-ylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 294 (MH⁺) 1644-amino-6-(4-chloro-naphthalen-1-ylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 328 (MH⁺) 1654-amino-6-(2,4-difluoro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 280 (MH⁺) 1664-amino-6-(2-methylsulfanyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 290 (MH⁺) 1674-amino-6-(3-fluoro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 262 (MH⁺) 1684-amino-6-(3,5-dichloro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 276 (MH⁺) 1694-amino-6-(3,5-dichloro-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 312 (MH⁺) 1704-amino-6-(5-chloro-2-methoxy-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 308 (MH⁺) 1714-amino-6-(5-chloro-2-methyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 292 (MH⁺) 1724-amino-6-(4-fluoro-phenylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 262 (MH⁺) 1734-amino-6-(biphenyl-4-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oximeMS m/z 320 (MH⁺) 1744-amino-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 290 (MH⁺) 1754-amino-6-(3,5-dimethoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 304 (MH⁺) 1764-amino-6-(3,4,5-trimethoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 334 (MH⁺) 1774-amino-6-(3,4-dimethoxy-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 304 (MH⁺) 1784-amino-6-(5,6,7,8-tetrahydro-naphthalen-1-ylamino)-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 298 (MH⁺) 1794-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-N-pyrimidin-2-yl-benzenesulfonamide MS m/z 401 (MH⁺) 1803-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzoic acidethyl ester MS m/z 316 (MH⁺) 181{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzyl}-phosphonicacid diethyl ester MS m/z 394 (MH⁺) 1824-amino-6-(4-ethyl-phenylamino)-pyrimidine-5-carbaldehyde O-methyl-oximeMS m/z 272 (MH⁺) 1834-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-N-(3,5-dimethyl-pyrazin-2-yl)-benzenesulfonamide MS m/z 429 (MH⁺) 1844-amino-6-(2-methyl-benzothiazol-5-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MS m/z 315 (MH⁺) 1854-amino-6-[4-(4-methoxy-phenylamino)-phenylamino]-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 365 (MH⁺) 1864-amino-6-(4-dimethylamino-phenylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 287 (MH⁺) 1874-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-N-(2-diethylamino-ethyl)-benzamide MS m/z 386 (MH⁺) 1884-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-benzoic acidbutyl ester MS m/z 344 (MH⁺) 1894-amino-6-(indan-4-ylamino)-pyrimidine-5-carbaldehyde O-methyl-oxime MSm/z 284 (MH⁺) 1904-amino-6-(4′-chloro-biphenyl-4-ylamino)-pyrimidine-5-carbaldehydeO-methyl- oxime MS m/z 354 (MH⁺) 1914-amino-6-[6-(4-fluoro-phenoxy)-pyridin-3-ylamino]-pyrimidine-5-carbaldehydeO-methyl-oxime MS m/z 355 (MH⁺) 1924′-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-ylamino]-biphenyl-4-carboxylic acid methyl ester MS m/z 378 (MH⁺)

EXAMPLE 24-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbonitrile(Cpd 118)

A solution of 4,6-dichloro-pyrimidine-5-carbonitrile Compound 2a (82 mg,0.47 mmol), Et₃N (0.13 mL, 0.94 mmol) and4-benzyloxy-3-chloro-phenylamine Compound 2b (110 mg, 0.47 mmol) in THF(4.7 mL) was stirred at 25° C. for 3 hours. The reaction mixture wasdiluted with EtOAc (50 mL), washed with water (1×50 mL) and concentratedto afford4-(4-benzyloxy-3-chloro-phenylamino)-6-chloro-pyrimidine-5-carbonitrileCompound 2c (175 mg, 100%) as an off-white solid; ¹H NMR (300 MHz,CD₃OD) δ 8.42 (s, 1H), 7.63 (s, 1H), 7.52-7.40 (m, 7H), 7.12 (m, 1H),5.22 (s, 2H), 5.19 (s, 2); MS (ESI) m/z: 373 (MH⁺).

A suspension of Compound 2c (10 mg, 0.027 mmol) in 2M NH₃ in MeOH (0.26mL) was warmed at reflux for 1 hour. The reaction mixture was cooled andconcentrated. The resulting residue was dissolved in EtOAc (25 mL) andwashed with water (15 mL). The organic layer was dried using Na₂SO₄ andconcentrated to afford Compound 118 (5 mg, 50%) as a yellow solid. ¹HNMR (400 MHz, CD₃OD) δ 8.05 (s, 1H), 7.57 (s, 1H), 7.48 (d, J=7.2 Hz,2H), 7.37-7.29 (m, 4H), 7.11 (d, J=8.8 Hz, 1H), 5.19 (s, 2).

Using the procedure of Example 2, other compounds representative of thepresent invention may be prepared:

Name4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-carbonitrile4-amino-6-[2-(3-fluoro-benzyl)-1H-benzoimidazol-5-ylamino]-pyrimidine-5-carbonitrile4-amino-6-[1-(3-fluoro-benzyl)-1H-indol-5-ylamino]-pyrimidine-5-carbonitrile 4-amino-6-(4-phenoxy-phenylamino)-pyrimidine-5-carbonitrile4-amino-6-(3-chloro-4-fluoro-phenylamino)-pyrimidine-5-carbonitrile

EXAMPLE 34-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-6-methylamino-pyrimidine-5-carbaldehydeO-methyl-oxime (Compound 39)

A solution of 4,6-dichloro-pyrimidine-5-carbaldehyde Compound 1a (100mg, 0.57 mmol) in CHCl₃ (1 mL) was treated with methylamine (0.31 mL,0.63 mmol, 2.0 M in THF) at RT under air. After 1 h the solvent wasremoved in vacuo and the product,4-chloro-6-methylamino-pyrimidine-5-carbaldehyde Compound 3a was used inthe next step without further purification. LC/MS (m/z) [M+1]⁺ 172(calculated for C₆H₆ClN₃O, 171.58).

Crude 4-chloro-6-methylamino-pyrimidine-5-carbaldehyde Compound 3a wasdissolved into DMSO (1 mL) and treated with3-chloro-4-(3-fluoro-benzyloxy)-phenylamine Compound 3b (157 mg, 0.63mmol). The resulting solution was heated to 90° C. for 2 h 40 min.Conversion of starting materials to4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-6-methylamino-pyrimidine-5-carbaldehydeCompound 3c was verified by LC/MS; (m/z) [M+1]⁺387 (calculated forC₁₉H₁₆ClFN₄O₂, 386.81). The reaction solution was carried on directly tothe next step without workup.

The reaction solution of Compound 3c was removed from the heating block,then methoxylamine hydrochloride (142 mg, 1.7 mmol) was added andheating resumed at 90° C. for 1 h. The crude reaction was cooled to RT,partitioned between EtOAc (30 mL) and H₂O (20 mL), the organic phase wasdried over Na₂SO₄, then concentrated in vacuo. Purification on theChromatotron radial, thin-layer chromatograph(http://www.chromatotron.com/chromatotron/specs.html) (1 mm, 20%EtOAc/CH₂Cl₂) afforded the product4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-6-methylamino-pyrimidine-5-carbaldehydeO-methyl-oxime Compound 39 as a yellow oil (4.7 mg, 0.01 mmol). ¹H NMR(300 Hz, CDCl₃) δ 8.99 (bs, 1H), 8.31 (bs, 1H), 8.26 (s, 1H), 7.54 (d,J=2.5 Hz, 1H), 7.38-7.17 (m, 4H), 7.04-6.90 (m, 2H), 5.13 (s, 2H), 3.97(s, 3H), 3.13 (d, J=4.9 Hz, 3H); LC/MS (m/z) [M+1]⁺ 416.1 (calculatedfor C₂₀H₁₉ClFN₅O₂, 415.85).

Using the procedure of Example 3, other compounds representative of thepresent invention were prepared:

Cpd Name and Data 40(5E)-4-ethylamino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 8.97 (bs, 1H), 8.23(s, 1H), 8.21 (bs, 1H), 8.02 (s, 1H), 7.83 (s, 1H), 7.37-7.23 (m, 4H),6.97-6.95 (m, 2H), 6.86-6.81 (m, 1H), 5.58 (s, 2H), 3.95 (s, 3H),3.63-3.59 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H); LC/MS (m/z) (MH⁺) 420.1(calculated for C₂₂H₂₂FN₇O, 419.46) 41(5E)-4-ethylamino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde O-ethyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 9.07 (bs, 1H), 8.24(s, 1H), 8.22 (bs, 1H), 8.02 (s, 1H), 7.83 (s, 1H), 7.34-7.23 (m, 4H),6.97-6.95 (m, 2H), 6.86-6.82 (m, 1H), 5.58 (s, 2H), 4.19 (q, J = 7.05,2H), 3.64-3.57 (m, 2H), 1.33-1.27 (m, 6H); LC/MS (m/z) (MH⁺) 434.2(calculated for C₂₃H₂₄FN₇O, 433.48) 42(5E)-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-6-ethylamino-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 8.86 (bs, 1H),8.24 (s, 2H), 7.56 (d, J = 2.61 Hz, 1H), 7.39-7.37 (m, 4H), 7.17-7.03(m, 1H), 6.93-6.90 (m, 1H), 6.44 (bs, 1H), 5.13 (s, 2H), 3.98 (s, 3H),3.59 (m, 2H), 1.28 (t, J = 7.23 Hz, 3H); LC/MS (m/z) (MH⁺) 430.1(calculated for C₂₁H₂₁ClFN₅O₂, 429.88) 43(5E)-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-6-ethylamino-pyrimidine-5-carbaldehyde O-ethyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 8.75 (bs, 1H),8.25 (s, 1H), 8.24 (s, 1H), 7.59 (d, J = 2.57 Hz, 1H), 7.35-7.18 (m,4H), 7.04-6.98 (m, 1H), 6.91-6.88 (m, 1H), 6.18 (bs, 1H), 5.12 (s, 2H),4.23 (q, J = 7.05 Hz, 2H), 3.56 (m, 2H), 1.35 (t, J = 7.05 Hz, 3H), 1.26(t, J = 7.14 Hz, 3H); LC/MS (m/z) (MH⁺) 444.1 (calculated forC₂₂H₂₃ClFN₅O₂, 443.90) 53(5E)-4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-6-methylamino-pyrimidine-5-carbaldehyde O-methyl-oxime ¹H NMR (300 Hz, CDCl₃) δ 8.65 (bs, 1H), 8.31(s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.85 (d, J = 1.74 Hz, 1H),7.39-7.22 (m, 3H), 6.97-6.94 (m, 2H), 6.41-6.37 (m, 1H), 5.57 (s, 2H),3.97 (s, 3H), 3.09 (d, J = 4.80 Hz, 3H); LC/MS (m/z) (MH⁺) 406.1(calculated for C₂₁H₂₀FN₇O, 405.43)

EXAMPLE 4(5E)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeO-(2-morpholin-4-yl-ethyl)-oxime (Cpd 78)

To a 100 L reactor equipped with nitrogen sweep, thermocouple andcondensers was added 2-methoxy-ethanol (66.5 kg),4-amino-6-chloro-pyrimidine-5-carbaldehyde Compound 1b (5.98 kg),4-benzyloxy-3-chloro-phenylamine Compound 1c (5.98 kg), 6N HCl (1.54 kg)and purified water (0.55 kg). The reactor wall was rinsed with2-methoxy-ethanol (0.5 kg). The slurry was heated to about 40° C. andaged for 15 minutes. A second addition of Compound 1c (3.09 kg) was madeand the reaction mixture was aged for an additional 15 minutes. Theslurry solution then crystallized. A third addition of Compound 1c (3.08kg) was made and the reaction mixture was aged for 15 minutes. Theslurry was heated to about 65° C. until HPLC analysis showed thereaction was complete, thus providing4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeCompound 1d which was used in the next step as an unisolatedintermediate.

The slurry containing Compound 1d was cooled to between about 20-25° C.,then O-(2-morpholin-4-yl-ethyl)-hydroxylamine dihydrochloride Compound4a (9.37 kg) and 6.0N NaOH solution (12.1 L) was added. The suspensionwas heated to reflux between about 105° C. to about 115° C. and thedistillate (between about 38.5 to about 43.5 kg) was collected. Theslurry was cooled to between about 20° C. to about 25° C., then2-methoxy-ethanol (18.5 kg) and purified water (19.1 kg) was added. Theresulting slurry was stirred for 0.5 h, then filtered on an 18″polypropylene filter lined with polypropylene cloth. The filter cake waswashed thrice with a mixture (1:1 v/v) of 2-methoxy-ethanol (15.1 kg)and water (13.9 kg). The wet cake was dried on the filter for at least30 minutes then transferred to polypropylene drying trays, weighed andcovered with polypropylene tray covers. The product was dried to aconstant weight at between about 55° C. to about 60° C. under vacuumwith a nitrogen bleed to provide Compound 78 (13.79 kg, 81% yield) as ayellow powder. 98.9 HPLC Area %, 99.6 HPLC wt. % vs. standard.

Compound 78 (11.00 kg), 1-propanol (44.2 kg) and water (55.0 kg) wasadded to a 100 L reactor equipped with nitrogen sweep, thermocouple, andcondensers. The resulting suspension was heated until a solution wasachieved (at about 70° C.). The solution was cooled to between about 60°C. to about 65° C. and the contents were polish filtered to another 100L reactor using a 145-175 micron filter. The solution was cooled toabout 10° C. over a period of about 3.5 hours and then aged for aboutone hour. The suspension was filtered on an 18″ polypropylene filterlined with polypropylene cloth and the resulting cake was washed twiceeach with a 1:1 (v/v) mixture of 1-propanol/water (19.8 kg). The filtercake was dried with nitrogen for at least 30 minutes on the filter andthen transferred to polypropylene drying trays, weighed and covered withpolypropylene tray covers. The product was dried to a constant weight atbetween about 55° C. to about 60° C. under vacuum with a nitrogen bleedto provide the mono hydrochloride salt of Compound 78 (9.60 kg, 87%yield) as a light yellow powder. 99.0 HPLC Area %, 99.8 HPLC wt. % vs.standard.

The present invention is further directed to a method for selectivelycoupling an aniline compound with a chlorinated pyrimidine aldehydecompound.

The first step of the foregoing Example 4 is representative of thismethod whereby an aniline compound reacts with a chlorinated pyrimidinealdehyde compound at the chloro substituted carbon atom instead of atthe aldehyde. This coupling is induced by using a catalytic amount ofacid. Acids that may be used in the present method include, and are notlimited to, aqueous HCl. Solvents that may be used in the present methodinclude, and are not limited to, 2-methoxy-ethanol.

EXAMPLE 5

N-(4-benzyloxy-3-chloro-phenyl)-5-[5-(2-morpholin-4-yl-ethyl)-[1,3,4]oxadiazol-2-yl]-pyrimidine-4,6-diamine(Cpd 193)

4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carbaldehydeCompound 1d (5.0 g, 14.1 mmol) in THF/MeOH (1/1, 125 mL) was treatedwith MnO₂ (7.4 g, 84.5 mmol), NaCN (2.1 g, 42.3 mmol), AcOH (2.4 mL,42.3 mmol) and the reaction mixture was warmed at reflux for 24 h. Themixture was cooled to rt and filtered through Celite. The filtrate wasdiluted with H₂O (200 mL) and then extracted with a (1/1) mixture ofEtOAc/THF (3×100 mL). The resulting organic extracts were dried(Na₂SO₄), and concentrated to afford4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carboxylicacid hydrazide Compound 5a (4.33 g, 80%) as a yellow solid. ¹H NMR (300MHz, DMSO-d6) δ 10.26 (s, 1H), 8.05 (s, 1H), 7.86 (d, J=2.4 Hz, 1H),7.64 (br s, 2 H), 7.51-7.35 (m, 7H), 7.20 (d, J=8.7 Hz, 1H), 5.22 (s,2H), 3.89 (s, 3H).

A suspension of Compound 5a (4.3 g, 11.2 mmol) in 100% EtOH (110 mL) wastreated with hydrazine (6.8 mL, 224 mol) and warmed at reflux for 24 h.The reaction mixture was concentrated onto SiO₂ (15 g). The residue waspurified via column chromatography (Horizon 65+M, 0-10% MeOH/DCM) toprovide4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carboxylicacid hydrazide Compound 5b (2.50 g, 58%) as a yellow solid. ¹H NMR (300MHz, CD₃OD) δ 7.96 (s, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.64-7.22 (m, 6H),7.04 (d, J=8.7 Hz, 1H), 5.22 (s, 2H); MS m/z 385.0 (MH⁺).

A mixture of Compound 5b (6.8 mg, 0.018 mmol),3-morpholin-4-yl-propionic acid hydrochloride (3.8 mg, 0.019 mmol) andEDCI (10.2 mg, 0.053 mmol) in DMF (0.17 mL) was stirred at rt for 12 h.The reaction was diluted with H₂O (20 mL) and extracted with EtOAc (3×10mL). The combined organic extracts were dried (Na₂SO₄) and concentratedto afford4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carboxylicacid N′-(3-morpholin-4-yl-propionyl)-hydrazide Compound 5c (8.3 mg, 88%)as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.03 (s, 1H), 7.76 (d,J=1.2 Hz, 1H), 7.47-7.30 (m, 6H), 7.05 (d, J=6.4 Hz, 1H), 5.15 (s, 2H),2.76 (m, 2H), 2.56 (m, 6H), 1.29 (br s, 6H); MS m/z 526.5 (MH⁺).

A solution of Compound 5c (6.2 mg, 0.012 mmol) in DCM (0.20 mL) wastreated with Et₃N (3.3 μL), then toluene sulfonyl chloride (2.4 mg,0.012 mmol) was added and the resulting solution was stirred at rt for 3h. The reaction was loaded directly onto a SiO₂ column (Horizon 12+M,0-5% MeOH/DCM) to afford Compound 193 (5.0 mg, 85%) as a white solid. ¹HNMR (400 MHz, CD₃OD) δ 8.09 (s, 1H), 7.75 (d, J=2.7 Hz, 1H), 7.47-7.32(m, 6H), 7.13 (d, J=9.0 Hz, 1H), 5.17 (s, 2H), 3.67 (m, 4H), 3.29 (t,J=1.5 Hz, 2H), 2.87 (t, J=6.9 Hz, 2H), 2.55 (m, 4H); MS m/z 508.2 (MH⁺).

BIOLOGICAL EXAMPLES

The ability of the compounds for treating, preventing or ameliorating achronic or acute kinase mediated disease, disorder or condition wasdetermined using the following procedures.

Example 1

EGFR Kinase Assay

The EGFR kinase used was a fusion of Glutathione-S-Transferase (GST) anda PCR amplified intracellular portion of EGFR (NM_(—)005228). Theintracellular portion of EGFR started at nucleotide 2189 (correspondingto amino acid 667) and ended at the termination codon. The portion wasPCR amplified with primers that added the lambda attB sequences to eachend, recombined into an entry vector, then into a GST destination vector(as described in Gateway Technologies Manual by Invitrogen Corporation,Carlsbad, Calif.).

The destination vector was recombined in the DH10BAC strain of bacteriato produce a bacmid. The bacmid was transfected into Sf 9 cells and thesupernatant containing the baculovirus was collected. The GSTEGFRprotein was purified using large cultures of Sf 9 cells infected withstock virus. After an appropriate period of time, the cells werecollected and lysed. The GSTEGFR was then purified from the lysate onGlutathione-Sepharose columns (as described by Amersham Biosciences,Buckinghamshire, United Kingdom).

The EGFR substrate was prepared by biotinylating polyGluTyr (128 mg)(Sigma™, St. Louis, Mo.) in a 1×PBS buffer incubated together with a12-fold molar excess of Sulfo-NHS-LC-Biotin on ice for at least 2 hrs.The free biotin was separated from the biotinylated polyGluTyr on a gelfiltration column.

A mixture of a 10× kinase buffer (500 mM Tris at pH 8.0, 100 mMMagnesium Chloride and 1 mM Sodium Vanadate), DTT (1 mM final from 500mM stock), ATP (5 μM final from 10 mM stock), biotinylated polyGluTyr(10 μg/μL stock), γ-³³P ATP (10 μCi/μL stock) and water was added toeach well (90 μL/well) of a Streptavidin Flashplate (Perkin Elmer,Wellesley, Mass.).

Test compound in 100% DMSO (2 μL) was added to the appropriate wells.Diluted GSTEGFR (1:300 dilution in 50 mM Tris at pH 8.0 and 0.1% bovineserum albumin) (10 μL) was added to the wells to initiate the reactions.

The plates were incubated at 30° C. for 1 hr with shaking. The reactedcontents were removed and the plates were sequentially washed threetimes with a 1×PBS stop buffer (300 μL without Magnesium and Calcium)and 100 mM EDTA. After the final wash, the same stop buffer (200 μL) wasadded to the wells. The plates were then sealed and read on the TopCountscintillation counter.

Test compounds were assayed in triplicate at 16 concentrations athalf-log dilutions starting at 200 μM. A maximum and minimum signal forthe assay was determined on each plate. The percent inhibition of a testcompound was calculated according to the formula

${\left\lbrack \frac{\left( {{\max\mspace{14mu}{signal}} - {{test}\mspace{14mu}{compound}}} \right)}{\left( {{\max\mspace{14mu}{signal}} - {\min\mspace{14mu}{signal}}} \right)} \right\rbrack(100)} = {\%\mspace{14mu}{inhibition}}$

For a series of test concentrations, the IC₅₀ was derived by graphingpercent inhibition against the log of the concentrations tested for agiven compound. The EGFR IC₅₀ results are shown in Table 1. Values shownas % indicate % inhibition at a test concentration of 2 μM.

TABLE 1 EGFR IC₅₀ (μM) Cpd IC₅₀ 1 0.07 2 0.008 3 1.1 4 0.01 5 0.5 7 0.059 0.02 10 0.005 11 0.008 12 0.04 13 0.2 14 0.1 16 0.01 17 0.02 18 0.0319 0.02 20 1.2 21 1.5 22 0.3 23 1.9 24 0.09 25 0.03 28 0.9 29 0.2 300.03 31 0.02 32 0.01 33 0.02 34 0.01 36 0.02 37 0.02 38 0.1 41 0.4 427.8 43 1.4 44 0.07 45 0.05 46 0.02 47 0.01 48 0.04 49 0.03 50 0.02 510.04 54 0.02 55 0.04 56 0.3 57 0.2 58 0.03 59 0.05 60 0.05 61 0.2 62 0.263 1.2 65 0.04 66 0.1 67 0.1 68 0.01 69 0.01 70 0.02 71 0.01 74 0.06 750.008 76 0.01 77 0.02 78 0.02 79 0.008 80 0.3 82 0.2 84 0.01 85 0.02 870.03 88 0.009 91 0.007 92 0.05 93 0.02 94 0.02 95 0.05 96 0.06 97 0.0398 0.02 99 0.07 100 0.02 102 0.04 108 0.2 111 0.1 112 0.02 118 0.03 12015% 122  6% 123  7% 124 26% 125 42% 128 45% 129  1%

Example 2

HER-2 Kinase Assay

The HER-2 kinase used was purified at Proqinase (Freiburg, Germany) froma construct that consisted of a fusion of GST(Glutathione-S-Transferase), HIS6-Thrombin and the nucleotides encodingamino acids 679 to 1255 of HER-2 (Accession Number M11730).

A mixture of a 10× kinase reaction buffer (600 mM Hepes at pH 7.5, 30 mMMagnesium Chloride, 0.03 mM Sodium Vanadate and 500 μg/mL PEG 20,000),DTT (1.2 mM final from a 10 mM stock), ATP (1 μM from a 10 mM stock),biotinylated polyGluTyr (1.5 ng/4 final from stock of 1 μg/μL) preparedby Upstate Biotechnologies, Lake Placid, N.Y.), Manganese Chloride (3 mMfinal from a 1 M stock), γ-³³P-ATP (10 μCi/μL stock) and water (70μL/well) was added to each well of a Streptavidin Flashplate (Cat. #SMP103, NEN, Boston, Mass.).

Test compound stock (1 μL) was added to the appropriate wells. DilutedGSTHER2 kinase (6.7 ng/μL diluted into 50 mM Tris-HCl at pH 8.0 and 0.1%bovine serum albumin) (30 μL) was added (total volume of 200 ng/well) toinitiate the reactions.

The reaction plates were incubated at 30° C. for 1 hr. The reaction wasterminated by aspirating the reaction mixture from the plate wells andwashing the wells three times with a 1×PBS stop buffer (300 μL) and 100mM EDTA. After the final wash, the same stop buffer (200 μL) was againadded to the wells. The plates were then sealed and read on the TopCountscintillation counter.

Test compounds were assayed in triplicate at 8 concentrations at one-logdilutions starting at 100 μM. A maximum and minimum signal for the assaywas determined on each plate. The percent inhibition of a test compoundwas calculated according to the formula:

${\left\lbrack \frac{\left( {{\max\mspace{14mu}{signal}} - {{test}\mspace{14mu}{compound}}} \right)}{\left( {{\max\mspace{14mu}{signal}} - {\min\mspace{14mu}{signal}}} \right)} \right\rbrack(100)} = {\%\mspace{14mu}{inhibition}}$

For a series of test concentrations, the IC₅₀ was derived by graphingpercent inhibition against the log of the concentrations tested for agiven compound. The Her-2 IC₅₀ values are shown in Table 2. Values shownas % indicate % inhibition at a test concentration of 1 μM.

TABLE 2 HER2 IC₅₀ (μM) Cpd IC₅₀ 1 0.2 2 0.01 3 5.2 4 0.02 5 3.7 6 0.1 70.1 8 0.7 9 0.2 10 0.007 11 0.01 12 0.05 13 0.1 14 3.1 15 100 16 0.01 170.6 18 0.04 19 0.05 20 14.1 21 5.3 22 4.1 23 28.5 24 0.2 25 0.3 26 10027 100 28 5.5 29 0.2 30 0.2 31 0.3 32 0.09 33 0.1 34 0.03 35 100 36 0.637 0.09 38 0.05 39 14.8 40 10.6 41 3.6 42 100 43 10.4 44 1.6 45 0.4 460.1 47 0.03 48 0.02 49 0.01 50 0.04 51 0.04 52 4.5 53 10.0 54 0.03 550.03 60 0.08 63 1.0 64 100 65 0.2 66 0.2 67 0.2 68 0.006 69 0.004 700.02 71 0.05 72 100 73 2.9 74 0.3 75 0.009 76 0.03 77 0.1 78 0.06 790.01 80 100 81 100 82 100 83 100 84 0.04 85 0.02 86 100 87 0.07 88 0.0289 10.0 90 100 91 0.03 92 0.03 93 0.008 94 0.04 95 0.2 96 0.1 97 1.0 980.1 99 0.2 100 10.0 101 0.06 102 0.14 103 100 104 100 105 100 106 100107 10.0 108 1.1 109 100 110 10.0 111 0.3 118 0.1 119 >10 120 7.923121 >10 122 >100 123 >100 124 2.46 125 25% 128 1.822 129 >100

Example 3

In Vitro Cell Proliferation Inhibition Assays

The ability of a test compound to inhibit unregulated in vitro cellproliferation may be determined by measuring incorporation of¹⁴C-labelled thymidine into newly synthesized DNA within cell linesderived from carcinomas originating from several tissues. Accordingly,the effect of a test compound on proliferation of cells with a varietyof phenotypes may be determined.

Carcinoma cell lines used include the HeLa cervical adenocarcinoma fromthe American Type Culture Collection (ATCC Cat. #CCL2), SK-OV-3 ovariancarcinoma (ATCC Cat. #HTB-77), MCF-7 breast carcinoma (ATCC Cat. #HTB-22), BT474 breast carcinoma (ATCC Cat. #HTB-20), SKBR3 breastcarcinoma (ATCC Cat. #HTB-30), A431 epidermoid carcinoma (ATCC Cat.#CRL-1555) and NCI-N87 gastric carcinoma (ATCC Cat. #CRL-5822).

The carcinoma cells are trypsinized and counted. The cells (3000-8000count) are added to each well of a 96-well CytoStar tissue culturetreated scintillating microplate (Amersham #RPNQ0160) in complete medium(100 μL) and the plate is then incubated in complete medium for 24 hrsat 37° C. in an inert atmosphere containing 5% CO₂.

Test compound (1 μL) in 100% DMSO is added to the plate test-wells withDMSO only added to control-wells. The plate is incubated in completemedium for a second 24 hr period at 37° C. in an atmosphere containing5% CO₂.

An aliquot of a solution of Methyl ¹⁴C-thymidine (56 mC/mmol) (NEN#NEC568 or Amersham #CFA532) and complete medium (20 μL to provide 0.2μCi/well) is then added to each well and the plate is incubated for athird 24 hr period at 37° C. in an atmosphere containing 5% CO₂.

The plate contents are then discarded, the plate is washed twice withPBS (200 μL) and then PBS (200 μL) is added to each well. The plate issealed and the degree of methyl ¹⁴C-thymidine incorporation isquantified on a Packard Top Count.

Cell proliferation of the Hela cell line was measured using the ATP-Litemethod as described in the ATP Lite Kit (Perkin-Elmer Kit Number6106941) or the C¹⁴ method as described above. Cell proliferation of theother cell lines was measured using the C¹⁴ method.

The IC₅₀ values for the compounds tested in various cell lines are shownin Tables 3 and 4. The term “NT” means that the compound indicated wasnot tested in a particular cell line. The lack of such testing is notintended to imply a belief that the compound is not otherwise active ina particular cell line or any other cell line not tested.

TABLE 3 HeLa IC₅₀ (μM) Cpd IC₅₀ 9 35.0 19 10.0 34 3.5 46 100 60 10.0 7010.0 75 40.1 76 59.4 77 10.0 78 19.6 79 100 80 100 81 10.0 82 100 83 3.684 4.9 85 15.6 86 100 87 4.9 88 10.9 89 10.0 90 10.0 91 9.4 92 4.7 9322.1 94 6.1 95 12.1 96 14.7 97 100 98 100 99 100 100 10.0 101 25.1 1021.4 103 10.0 104 10.0 105 100 106 10.0 107 100 108 10.0 109 100 110 33.1118 100

TABLE 4 IC₅₀ (μM) Cpd SK-OV-3 MCF-7 BT474 SKBR3 N87 A431 9 100 86.6 NTNT 0.7 NT 19 19.1 2.5 0.03 0.1 0.04 1.1 34 3.2 3.8 NT NT 0.2 NT 46 NT NT0.1 0.3 10.0 100 60 10.0 10.0 NT NT 0.6 NT 70 NT NT 0.1 0.4 0.3 14.2 7510.0 30.7 NT NT 0.001 NT 76 24.1 10.0 0.2 0.3 0.3 1.8 78 100 100 0.060.2 0.2 0.8 87 NT NT 0.3 0.5 0.3 3.6 91 5.4 10.0 0.2 0.3 0.2 1.3 92 NTNT 0.2 0.4 0.2 3.1 93 100 100 0.04 0.02 0.07 0.6 94 1.0 1.0 0.5 0.5 0.4NT 95 2.4 1.0 10.0 10.0 1.1 100 96 15.3 2.1 0.2 0.4 0.2 0.8 99 NT NT10.0 100 100 100 101 NT NT 0.05 0.06 0.03 0.009 102 NT NT 0.9 0.7 0.20.001 118 NT NT 100 100 100 100

Example 4

N87 Human Tumor Xenograft Model

The N87 gastric carcinoma cell line overexpresses HER-2 as a result ofgene amplification and forms tumors in nude mice (Kasprzyk P G, Song SU, Di Fiore P P, King C R, Therapy of an animal model of human gastriccancer using a combination of anti-erbB-2 monoclonal antibodies, CancerRes., 1992, 52, 2771-2776).

Female nu/nu mice (Charles River; 8 to 9 weeks of age) were implantedsubcutaneously with from 3×10⁶ to 5×10⁶ N87 gastric carcinoma cells(obtained from the American Type Culture Collection, ATCC Cat.#CRL-5822) in the flank. Animals were weighed twice weekly during thestudy and examined frequently.

Tumor size was monitored twice weekly and then daily as the neoplasmsreached the target weight range (about 75 mg). Animals were pair-matchedwhen tumors were in the 62 to 126 mg range (group mean tumor size: 70 to74 mg). Estimated tumor weight was calculated using the formula:

${{Tumor}\mspace{14mu}{Weight}} = \frac{\left( {width}^{2} \right)({length})}{2}$

A test compound was orally administered daily in the test treatmentgroup after the tumor reached the target weight. For treatment group 1,the test compound was administered once daily for 35 days. For treatmentgroup 2, the test compound was administered once daily for 30 days. Fortreatment group 3, each dose of test compound was administered oncedaily for 30 days. For treatment group 4, each dose of test compound wasadministered once daily for 36 days. For treatment group 5-10, the testcompound was administered once daily for 30 days.

Tumor weight was measured daily for subjects (n=8) in the test group andthe matched subjects (n=8) in the vehicle-treated group.

The tumor growth inhibition (in percent) was calculated on the last dayof the study using the formula:

${{Tumor}\mspace{14mu}{Growth}\mspace{14mu}{Inhibition}} = {X\mspace{14mu} 100\%\frac{\begin{pmatrix}{{mean}\mspace{14mu}{tumor}\mspace{14mu}{weight}} \\{{vehicle}\mspace{14mu}{group}}\end{pmatrix} - \begin{pmatrix}{{mean}\mspace{14mu}{tumor}\mspace{14mu}{weight}} \\{{test}\mspace{14mu}{group}}\end{pmatrix}}{{mean}\mspace{14mu}{tumor}\mspace{14mu}{weight}\mspace{14mu}{vehicle}\mspace{14mu}{group}}}$

The results for the study are shown in Table 5. Statistical significancewas evaluated by comparing the vehicle group to the test group using atwo tailed Students t test. The term “NC” means that the P value for thetreatment group indicated was not calculated. The lack of suchcalculation is not intended to imply a belief that the activity of thecompound is not otherwise statistically significant in this particularcell line or in any other cell line not tested.

TABLE 5 N87 Tumor Growth Inhibition Treatment Dose Group Cpd (mg/kg) TGIP value 1 78 100 71.0% 0.006 2 78 100 69.4% 0.003 3 78 100 59.56%  0.0443 78 50 50.56%  0.025 3 78 25 41.29%  0.023 4 78 100 49.3% 0.007 4 78 5033.9% 0.02 4 78 25  6.5% 0.04 5 93 100 59.9% NC 6 94 100 47.1% NC 7 101100   66% NC 8 112 100 48.6% NC 9 114 100   47% NC 10 115 100 50.2% NC

Example 5

A431 Human Tumor Xenograft Model

The A431 epidermoid carcinoma cell line overexpresses EGFR, activatingsignaling pathways responsible for driving the proliferation, invasionand survival of cancer cells and forming tumors in nude mice (Giard D J,Aaronson S A, Todaro G J, Arnstein P, Kersey J H, Dosik H, Parks W P, Invitro cultivation of human tumors: establishment of cell lines derivedfrom a series of solid tumors, J. Natl. Cancer Inst., 1973, 51,1417-1423; and, Kawamoto T, Sato J D, Le A, Polikoff J, Sato G H,Mendelsohn J, Growth stimulation of A431 cells by epidermal growthfactor: identification of high-affinity receptors for epidermal growthfactor by an anti-receptor monoclonal antibody, Proc. Natl. Acad. Sci.USA, 1983, 80, 1337-1341).

Female nu/nu mice (Charles River; 8 to 9 weeks of age) were implantedsubcutaneously in the flank with 4×10⁶ A431 epidermoid carcinoma cells(obtained from the American Type Culture Collection, ATCC Cat.#CRL-1555). Animals were weighed twice weekly during the study andexamined frequently.

Tumor size was monitored twice weekly and then daily as the neoplasmsreached the target weight range (about 75 mg). Animals were pair-matchedwhen tumors were in the 62 to 126 mg range (group mean tumor size: 70 to74 mg). Estimated tumor weight was calculated using the formula ofExample 4.

A test compound was orally administered daily in the test treatmentgroup after the tumor reached the target weight. For treatment groups 1and 2, each dose of test compound was administered once daily for 25days. For treatment group 3, each dose of test compound was administeredtwice daily for 25 days. For treatment group 4, the test compound wasadministered twice daily for 30 days. For treatment group 5-10, the testcompound was administered once daily for 30 days.

Using the formula of Example 4, tumor weight was measured daily forsubjects (n=8) in the test group and the matched subjects (n=8) in thevehicle-treated group. Using the formula of Example 4, tumor growthinhibition (in percent) was calculated on the last day of the study.

The results for the study are shown in Table 6. Statistical significancewas evaluated by comparing the vehicle group to the test group using atwo tailed Students t test. The term “NC” means that the P value for thetreatment group indicated was not calculated. The lack of suchcalculation is not intended to imply a belief that the activity of thecompound is not otherwise statistically significant in this particularcell line or in any other cell line not tested.

TABLE 6 A431 Tumor Growth Inhibition Treatment Dose Group Cpd (mg/kg)TGI P value 1 78 100 66.8% 0.025 1 78 30 10.6% 0.553 2 78 100 34.6%0.216 2 78 50 14.3% 0.571 3 78 100 51.1% 0.038 3 78 50 45.12%  0.106 478 100   52% 0.048 5 93 100 64.0% NC 6 94 100   66% NC 7 101 100   51%NC 8 112 100   33% NC 9 114 100   −3% NC 10 115 100   4% NC

Example 6

BT474 Human Tumor Xenograft Model

The BT474 human tumor cell line overexpresses HER-2 and forms tumors inimmunocompromised mice (Rabindran S K, Discafani C M, Rosfjord E C,Baxter M, Floyd M B, Golas J, Hallett W A, Johnson B D, Nilakantan R,Overbeek E, Reich M F, Shen R, Shi X, Tsou H R, Wang Y F and Wissner A,Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitorof the HER-2 Tyrosine Kinase, Cancer Res., 2004, 64, 3958-3965).

Immunocompromised CB.17 SCID female mice were subcutaneously implantedin the hindflank with 1 mm³ BT474 breast carcinoma tumor fragments.Animals were weighed twice weekly during the study and examinedfrequently.

Tumor size was monitored twice weekly and then daily as the neoplasmsreached the target weight range (about 75 mg). Animals were pair-matchedwhen tumors were in the 62 to 126 mg range (group mean tumor size: 70 to74 mg). Estimated tumor weight was calculated using the formula ofExample 4.

A test compound was orally administered daily in the test treatmentgroup after the tumor reached the target weight. For treatment group 1,each dose of test compound was administered once daily for 25 days. Fortreatment groups 2 and 3, each dose of test compound was administeredtwice daily for 30 days.

Using the formula of Example 4, tumor weight was measured daily forsubjects (n=15 for group 1, n=10 for groups 2 and 3) in the test groupsand the matched subjects (n=8) in the vehicle-treated group. Using theformula of Example 4, tumor growth inhibition (in percent) wascalculated on the last day of the study.

The results for the study are shown in Table 7. Statistical significancewas evaluated by comparing the vehicle group to the test group using atwo tailed Students t test.

TABLE 7 BT474 Tumor Growth Inhibition Treatment Dose Group Cpd (mg/kg)TGI P value 1 78 50 27% 0.100 2 78 100 52% 0.004 3 78 200 62% 0.035

Example 7

Blood-Brain Barrier Penetration

The blood-brain barrier penetration of Compound 78 was examined in maleSprague Dawley rats following i.v. (3 mg/kg) or oral (10 mg/kg)administration.

The i.v. formulation consisted of a 1 mg/mL dose in vehicle (10% solutolin D5W at pH 3) with plasma samples drawn at 0.25 hours, 0.5 hours and 1hour after administration.

The oral (p.o) formulation consisted of a 1 mg/mL dose in vehicle (0.5%methylcellulose) with plasma samples drawn at 0.5 hours, 1 hour and 2hours after administration.

The plasma samples (0.5 ml) were collected and centrifuged (2000 rpm, 3min), then stored at −60° C. until LC-MS/MS analysis. Brain samples werecollected immediately after the last blood sample collection. Thesamples were rinsed with 0.9% NaCl, patted dry, then weighed and placedin Falcon 14 mL polypropylene round-bottom tubes containing 3 mLmethanol. The methanolic mixtures were homogenized with an OMNI TH115homogenizer then centrifuged for 10 minutes at 7,000 rpm. Thesupernatant was removed and stored frozen in 15 mL polyethylene tubes at−60° C. until LC-MS/MS analysis.

TABLE 8 Concentration in Plasma (ng/mL) and Brain (ng/g) AdministrationMean ± SEM Brain/Plasma Ratio p.o. 60 min (plasma) 73.6 ± 16.4 1.2 p.o.120 min (brain) 46.1 ± 17.4 p.o. 120 min (brain) 51.16 ± 13.71 i.v. 60min (plasma) 124.1 ± 5.5  2.5 i.v. 60 min (brain) 306.9 ± 55  

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and modifications as come within thescope of the following claims and their equivalents.

Throughout this application, various publications are cited. Thesepublications are hereby incorporated by reference in their entirety intothis application to describe more fully the state of the art to whichthis invention pertains.

1. A compound of Formula (I)

or a salt, stereoisomer, or tautomer thereof, wherein L is a bond,C₁₋₆alkyl or halo-C₁₋₆alkyl; Ar is aryl, heteroaryl,benzofused-heterocyclyl or benzofused-C₃₋₁₂cycloalkyl; R_(A) is—CH═N—O—R₁ or cyano or an R₁ substituted oxadiazole; R₁ is hydrogen,C₁₋₈alkyl, C₁₋₈alkenyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy, amino-C_(1-8 l alkyl, C)₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl,aryl-C₁₋₈alkyl, aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,heterocyclyl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl orheteroaryl-C₁₋₈alkyl, wherein aryl-C₁₋₈alkyl is optionally substitutedon aryl with one, two, three, four or five substituents that are eachhydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino orC₁₋₈alkoxycarbonyl, and wherein heterocyclyl-C₁₋₈alkyl is optionallysubstituted on heterocyclyl with one, two, three or four substituentsthat are each hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino orC₁₋₈alkoxycarbonyl; R₂ is hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and R₃, R₄,R₅, R₆ and R₇ is each hydrogen, halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl, amino,C₁₋₈alkyl-amino, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl, C₁₋₈alkoxy-imino-C₁₋₈alkyl,C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl, carboxy, C₁₋₈acyl, C₁₋₈acyl-amino,C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl, substituted phosphonic acid,C₃₋₁₂cycloalkyl, aryl, aryloxy, aryl-amino, aryl-C₁₋₈alkyl,aryl-C₁₋₈alkoxy, aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryl,heteroaryloxy, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,benzofused-heterocyclyl or heterocyclyl, wherein phosphonic acid issubstituted on the phosphorous atom with two substituents that are eachhydroxy or C₁₋₈alkoxy, wherein aryl, aryloxy, aryl-amino, aryl-C₁₋₈alkyland aryl-C₁₋₈alkoxy are each optionally substituted on aryl with one,two, three, four or five substituents that are each cyano, halogen,hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl or C₁₋₈alkoxycarbonyl, whereinbenzofused-heterocyclyl is optionally substituted on the heterocyclylportion with one or two oxo substituents, and wherein heteroaryl,heteroaryl-amino-sulfonyl and heteroaryloxy is each optionallysubstituted on heteroaryl with one, two, three, four or fivesubstituents that are each C₁₋₈alkyl, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl or C₁₋₈alkoxycarbonyl.
 2. Acompound of Formula (II):

or a salt, stereoisomer, or tautomer thereof, wherein L is a bond,C₁₋₆alkyl or halo-C₁₋₆alkyl; Ar is aryl, heteroaryl,benzofused-heterocyclyl or benzofused-C₃₋₁₂cycloalkyl, wherein thebenzene ring portion of the benzofused ring system is attached to the Lvariable; R_(A) is —CH═N—O—R₁ or cyano; R₁ is hydrogen, C₁₋₈alkyl,C₁₋₈alkenyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl,C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,heterocyclyl-carbonyl-C₁₋₈alkyl or heteroaryl-C₁₋₈alkyl, whereinaryl-C₁₋₈alkyl is optionally substituted on aryl with one, two, three,four or five substituents that are each hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy,amino, C₁₋₈alkyl-amino or C₁₋₈alkoxycarbonyl, and whereinheterocyclyl-C₁₋₈alkyl is optionally substituted on heterocyclyl withone, two, three or four substituents that are each hydroxy, C₁₋₈alkyl,C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino or C₁₋₈alkoxycarbonyl; R₂ ishydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and R₃, R₄, R₅, R₆ and R₇ is eachhydrogen, halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy,amino, C₁₋₈alkyl-amino, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,carboxy, C₁₋₈acyl, C₁₋₈alkoxycarbonyl, C₃₋₁₂cycloalkyl, aryl, aryloxy,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy, aryl-amido, heteroaryl, heteroaryloxy,heteroaryl-C₁₋₈alkoxy or heterocyclyl, wherein aryl, aryloxy,aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy is each optionally substituted onaryl with one, two, three, four or five substituents that are eachcyano, halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl or C₁₋₈alkoxycarbonyl, andwherein heteroaryl and heteroaryloxy is each optionally substituted onheteroaryl with one, two, three, four or five substituents that are eachC₁₋₈alkyl, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acylor C₁₋₈alkoxycarbonyl.
 3. A compound of formula (Ic):

or a salt, stereoisomer, or tautomer thereof, wherein L is a bond,C₁₋₆alkyl or halo-C₁₋₆alkyl; Ar is aryl, heteroaryl,benzofused-heterocyclyl or benzofused-C₃₋₁₂cycloalkyl; R₂ is hydrogen,C₁₋₈alkyl or C₁₋₈alkoxy; and R₃, R₄, R₅, R₆ and R₇ is each hydrogen,halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy,cyano-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl,C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl, carboxy,C₁₋₈acyl, C₁₋₈acyl-amino, C₁₋₈C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl,substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl, aryloxy, aryl-amino,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy, aryl-carbonyl-C₁₋₈alkyl, aryl-amido,heteroaryl, heteroaryloxy, heteroaryl-C₁₋₈alkoxy,heteroaryl-amino-sulfonyl, benzofused-heterocyclyl or heterocyclyl,wherein phosphonic acid is substituted on the phosphorous atom with twosubstituents that are each hydroxy or C₁₋₈alkoxy, wherein aryl, aryloxy,aryl-amino, aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy is each optionallysubstituted on aryl with one, two, three, four or five substituents thatare each cyano, halogen, hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino,C₁₋₈alkyl-amino, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl orC₁₋₈alkoxycarbonyl, wherein benzofused-heterocyclyl is optionallysubstituted on the heterocyclyl portion with one or two oxosubstituents, and wherein heteroaryl, heteroaryl-amino-sulfonyl andheteroaryloxy is each optionally substituted on heteroaryl with one,two, three, four or five substituents that are each C₁₋₈alkyl,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl orC₁₋₈alkoxycarbonyl. wherein heteroaryl-amino-sulfonyl and heteroaryloxyis each optionally substituted on heteroaryl with one or two C₁₋₈alkylsubstituents.
 4. A compound of formula (Id):

or a salt, stereoisomer, or tautomer thereof, wherein L is a bond,C₁₋₆alkyl or halo-C₁₋₆alkyl; R₂ is hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy;and R₃, R₄, R₅, R₆ and R₇ is each hydrogen, halogen, hydroxy, C₁₋₈alkyl,C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, halo-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy, halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl, amino,C₁₋₈alkyl-amino, amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino-carbonyl, C₁₋₈alkoxy-imino-C₁₋₈alkyl,C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl, carboxy, C₁₋₈acyl, C₁₋₈acyl-amino,C₁₋₈C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl, substituted phosphonic acid,C₃₋₁₂cycloalkyl, aryl, aryloxy, aryl-amino, aryl-C₁₋₈alkyl,aryl-C₁₋₈alkoxy, aryl-carbonyl-C₁₋₈alkyl, aryl-amido, heteroaryl,heteroaryloxy, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino-sulfonyl,benzofused-heterocyclyl or heterocyclyl, wherein phosphonic acid issubstituted on the phosphorous atom with two substituents that are eachhydroxy or C₁₋₈alkoxy, wherein aryl, aryl-amino, aryloxy, aryl-C₁₋₈alkyland aryl-C₁₋₈alkoxy is each optionally substituted on aryl with one,two, three, four or five substituents that are each cyano, halogen,hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl or C₁₋₈alkoxycarbonyl, whereinbenzofused-heterocyclyl is optionally substituted on the heterocyclylportion with one or two oxo substituents, and wherein heteroaryl,heteroaryl-amino-sulfonyl and heteroaryloxy is each optionallysubstituted on heteroaryl with one, two, three, four or fivesubstituents that are each C₁₋₈alkyl, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, carboxy, C₁₋₈acyl or C₁₋₈alkoxycarbonyl.
 5. Apharmaceutical composition comprising a pharmaceutical acceptableexcipient and an effective amount of a compound of claim
 1. 6. Thepharmaceutical composition of claim 5 wherein the effective amount ofthe compound is in a range of from about 0.001 mg/kg to about 300 mg/kgof body weight per day.
 7. A process for preparing a pharmaceuticalcomposition comprising the step of admixing a compound of claim 1 and apharmaceutically acceptable carrier.
 8. A method of treating rheumatoidarthritis in a subject in need thereof comprising administering to thesubject an effective amount of a compound of claim
 1. 9. A method oftreating breast cancer in a subject in need thereof comprisingadministering to the subject an effective amount of a compound ofclaim
 1. 10. The method of claim 8 further comprising administering thecompound in combination with at least one other therapeutic agent fortreating or ameliorating rheumatoid arthritis.
 11. A process forpreparing a compound of claim 1 comprising the steps of: a. reacting acompound of Formula A4 with NH₂OH hydrochloride to provide a compound ofFormula A5:

b. reacting a mixture of the compound of Formula A5 and a basic reagentwith a compound of Formula A6 (wherein Q1 is a halogen leaving group) toprovide a compound of Formula A7:

c. reacting the compound of Formula A7 with a compound of Formula A8(wherein Q2 is a halogen leaving group) to provide a compound of FormulaA9:

and d. converting the compound of Formula A9 to provide a compound ofFormula A10:

wherein L is a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl; Ar is aryl,heteroaryl, benzofused-heterocyclyl or benzofused-C₃₋₁₂cycloalkyl; R_(A)is —CH═N—O—R₁ or cyano or an R₁ substituted oxadiazole; R₁ is hydrogen,C₁₋₈alkyl, C₁₋₈alkenyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl,aryl-C₁₋₈alkyl, aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,heterocyclyl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl orheteroaryl-C₁₋₈alkyl, wherein aryl-C₁₋₈alkyl is optionally substitutedon aryl with one, two, three, four or five substituents that are eachhydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino orC₁₋₈alkoxycarbonyl, and wherein heterocyclyl-C₁₋₈alkyl is optionallysubstituted on heterocyclyl with one, two, three or four substituentsthat are each hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino orC₁₋₈alkoxycarbonyl; R₂ is hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and R₃, R₄,R₅, R₆ and R₇ is each hydrogen, halogen,C₁₋₈alkyl, C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, halo-C₁₋₈alkoxy,C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,substituted phosphonic acid, C₃₋₁₂cycloalkyl, aryl, aryloxy,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy, heteroaryl, heteroaryloxy,heteroaryl-C₁₋₈alkoxy, benzofused-heterocyclyl or heterocyclyl, whereinphosphonic acid is substituted on the phosphorous atom with twosubstituents that are each hydroxy or C₁₋₈alkoxy, wherein aryl, aryloxy,aryl-C₁₋₈alkyl and aryl-C₁₋₈alkoxy are each optionally substituted onaryl with one, two, three, four or five substituents that are eachcyano, halogen, C₁₋₈alkyl, or C₁₋₈alkoxy, whereinbenzofused-heterocyclyl is optionally substituted on the heterocyclylportion with one or two oxo substituents, and wherein heteroaryl andheteroaryloxy is each optionally substituted on heteroaryl with one,two, three, four or five substituents that are each C₁₋₈alkyl.
 12. Aprocess for preparing a compound of claim 1 comprising the step ofconverting a compound of Formula C4 to a compound of Formula C5:

wherein L is a bond, C₁₋₆alkyl or halo-C₁₋₆alkyl; Ar is aryl,heteroaryl, benzofused-heterocyclyl or benzofused-C₃₋₁₂cycloalkyl; R_(A)is —CH═N—O—R₁ or cyano or an R₁ substituted oxadiazole; R₁ is hydrogen,C₁₋₈alkyl, C₁₋₈alkenyl, C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,C₁₋₈alkyl-sulfonyl-C₁₋₈alkyl, C₁₋₈alkyl-sulfonyloxy-C₁₋₈alkyl, aryl,aryl-C₁₋₈alkyl, aryloxy-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl,heterocyclyl-carbonyl-C₁₋₈alkyl, benzofused-heterocyclyl-C₁₋₈alkyl orheteroaryl-C₁₋₈alkyl, wherein aryl-C₁₋₈alkyl is optionally substitutedon aryl with one, two, three, four or five substituents that are eachhydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino orC₁₋₈alkoxycarbonyl, and wherein heterocyclyl-C₁₋₈alkyl is optionallysubstituted on heterocyclyl with one, two, three or four substituentsthat are each hydroxy, C₁₋₈alkyl, C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino orC₁₋₈alkoxycarbonyl; R₂ is hydrogen, C₁₋₈alkyl or C₁₋₈alkoxy; and R₃, R₄,R₅, R₆ and R₇ is each hydrogen, halogen, C₁₋₈alkyl, C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl, halo-C₁₋₈alkyl, halo-C₁₋₈alkoxy, cyano-C₁₋₈alkyl,C₁₋₈alkoxy-imino-C₁₋₈alkyl, C₁₋₈alkoxy-imino-(aryl)C₁₋₈alkyl,C₁₋₈alkoxycarbonyl, thio-C₁₋₈alkyl, substituted phosphonic acid,C₃₋₁₂cycloalkyl, aryl, aryloxy, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy,heteroaryl, heteroaryloxy, heteroaryl-C₁₋₈alkoxy,benzofused-heterocyclyl or heterocyclyl, wherein phosphonic acid issubstituted on the phosphorous atom with two substituents that are eachhydroxy or C₁₋₈alkoxy, wherein aryl, aryloxy, aryl-C₁₋₈alkyl andaryl-C₁₋₈alkoxy are each optionally substituted on aryl with one, two,three, four or five substituents that are each cyano, halogen,C₁₋₈alkyl, or C₁₋₈alkoxy, wherein benzofused-heterocyclyl is optionallysubstituted on the heterocyclyl portion with one or two oxosubstituents, and wherein heteroaryl and heteroaryloxy is eachoptionally substituted on heteroaryl with one, two, three, four or fivesubstituents that are each C₁₋₈alkyl.
 13. The method of claim 9 furthercomprising administering the compound as an adjunct to chemotherapy andradiation therapy.